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Zhang X, Lan R, Liu Y, Pillarisetty VG, Li D, Zhao CL, Sarkar SA, Liu W, Hanna I, Gupta M, Hajdu C, Melamed J, Shusterman M, Widmer J, Allendorf J, Liu YZ. Complement activation in tumor microenvironment after neoadjuvant therapy and its impact on pancreatic cancer outcomes. NPJ Precis Oncol 2025; 9:58. [PMID: 40032924 PMCID: PMC11876354 DOI: 10.1038/s41698-025-00848-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 02/24/2025] [Indexed: 03/05/2025] Open
Abstract
Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC). This study investigates how NAT differentially impacts PDAC's carcinoma cells and the tumor microenvironment (TME). Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME of 23 NAT-treated versus 13 NAT-naïve PDACs. Findings were validated by single-nucleus RNA sequencing (snRNA-seq) analysis. NAT induces apoptosis and inhibits proliferation of carcinoma cells and coordinately upregulates multiple complement genes (C1R, C1S, C3, C4B and C7) within the TME. Higher TME complement expression following NAT is associated with increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4+ T cells; reduced immune exhaustion gene expression, and improved overall survival. snRNA-seq analysis demonstrates C3 complement is mainly upregulated in CAFs. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response, and guiding therapeutic strategies in NAT-treated PDAC patients.
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Affiliation(s)
- Xiaofei Zhang
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA.
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Mineola, NY, USA.
| | - Ruoxin Lan
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
| | - Yongjun Liu
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI, USA
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA, USA
| | - Venu G Pillarisetty
- Department of Surgery, University of Washington School of Medicine, Seattle, WA, USA
| | - Danting Li
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA
| | - Chaohui L Zhao
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - Suparna A Sarkar
- Department of Pathology and Laboratory Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Weiguo Liu
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - Iman Hanna
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - Mala Gupta
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - Cristina Hajdu
- Department of Pathology and Laboratory Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Jonathan Melamed
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - Michael Shusterman
- Department of Oncology, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - Jessica Widmer
- Department of Gastroenterology, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - John Allendorf
- Department of Surgery, New York University Grossman Long Island School of Medicine, Mineola, NY, USA
| | - Yao-Zhong Liu
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA, USA.
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Shah A, Ganguly K, Rauth S, Sheree SS, Khan I, Ganti AK, Ponnusamy MP, Kumar S, Jain M, Batra SK. Unveiling the resistance to therapies in pancreatic ductal adenocarcinoma. Drug Resist Updat 2024; 77:101146. [PMID: 39243602 PMCID: PMC11770815 DOI: 10.1016/j.drup.2024.101146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 08/15/2024] [Accepted: 08/23/2024] [Indexed: 09/09/2024]
Abstract
Despite the ongoing advances in interventional strategies (surgery, chemotherapy, radiotherapy, and immunotherapy) for managing pancreatic ductal adenocarcinoma (PDAC), the development of therapy refractory phenotypes remains a significant challenge. Resistance to various therapeutic modalities in PDAC emanates from a combination of inherent and acquired factors and is attributable to cancer cell-intrinsic and -extrinsic mechanisms. The critical determinants of therapy resistance include oncogenic signaling and epigenetic modifications that drive cancer cell stemness and metabolic adaptations, CAF-mediated stromagenesis that results in ECM deposition altered mechanotransduction, and secretome and immune evasion. We reviewed the current understanding of these multifaceted mechanisms operating in the PDAC microenvironment, influencing the response to chemotherapy, radiotherapy, and immunotherapy regimens. We then describe how the lessons learned from these studies can guide us to discover novel therapeutic regimens to prevent, delay, or revert resistance and achieve durable clinical responses.
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Affiliation(s)
- Ashu Shah
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Koelina Ganguly
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Sanchita Rauth
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Shamema S Sheree
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Imran Khan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Apar K Ganti
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Division of Oncology-hematology, Department of Internal Medicine, VA Nebraska Western Iowa Health Care System and University of Nebraska Medical Center, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Moorthy P Ponnusamy
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-5870, USA
| | - Sushil Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA
| | - Maneesh Jain
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-5870, USA.
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-5870, USA; Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha 68198-5870, USA.
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Ni R, Hu Z, Tao R. Advances of immune-checkpoint inhibition of CTLA-4 in pancreatic cancer. Biomed Pharmacother 2024; 179:117430. [PMID: 39260322 DOI: 10.1016/j.biopha.2024.117430] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 09/05/2024] [Accepted: 09/05/2024] [Indexed: 09/13/2024] Open
Abstract
Targeting checkpoints for immune cell activation has been acknowledged known as one of the most effective way to activate anti-tumor immune responses. Among them, drugs targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are approved for clinical treatment though several more are in advanced stages of development, which demonstrated durable response rates and manageable safety profile. However, its therapy efficacy is unsatisfactory in pancreatic cancer (PC), which can be limited by the overall condition of patients, the pathological type of PC, the expression level of tumor related genes, etc. To improve clinical efficiency, various researches have been conducted, and the efficacy of combination therapy showed significantly improvement compared to monotherapy. This review analyzed current strategies based on anti-CTLA-4 combination immunotherapy, providing totally new idea for future research.
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Affiliation(s)
- Ran Ni
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China; General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zhiming Hu
- The Second Clinical Medical College, Zhejiang Chinese Medical University, Hangzhou, China; Department of Hepatobiliary & Pancreatic Surgery, Tongde Hospital of Zhejiang Province, Hangzhou 310012, China.
| | - Ran Tao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
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Zhang X, Lan R, Liu Y, Pillarisetty VG, Li D, Zhao CL, Sarkar SA, Liu W, Hanna I, Gupta M, Hajdu C, Melamed J, Shusterman M, Widmer J, Allendorf J, Liu YZ. Enhanced Complement Expression in the Tumor Microenvironment Following Neoadjuvant Therapy: Implications for Immunomodulation and Survival in Pancreatic Ductal Adenocarcinoma. RESEARCH SQUARE 2024:rs.3.rs-4104258. [PMID: 38798691 PMCID: PMC11118688 DOI: 10.21203/rs.3.rs-4104258/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Background Neoadjuvant therapy (NAT) is increasingly being used for pancreatic ductal adenocarcinoma (PDAC) treatment. However, its specific effects on carcinoma cells and the tumor microenvironment (TME) are not fully understood. This study aims to investigate how NAT differentially impacts PDAC's carcinoma cells and TME. Methods Spatial transcriptomics was used to compare gene expression profiles in carcinoma cells and the TME between 23 NAT-treated and 13 NAT-naïve PDAC patients, correlating with their clinicopathologic features. Analysis of an online single-nucleus RNA sequencing (snRNA-seq) dataset was performed for validation of the specific cell types responsible for NAT-induced gene expression alterations. Results NAT not only induces apoptosis and inhibits proliferation in carcinoma cells but also significantly remodels the TME. Notably, NAT induces a coordinated upregulation of multiple key complement genes (C3, C1S, C1R, C4B and C7) in the TME, making the complement pathway one of the most significantly affected pathways by NAT. Patients with higher TME complement expression following NAT exhibit improved overall survival. These patients also exhibit increased immunomodulatory and neurotrophic cancer-associated fibroblasts (CAFs); more CD4+ T cells, monocytes, and mast cells; and reduced immune exhaustion gene expression. snRNA-seq analysis demonstrates C3 complement was specifically upregulated in CAFs but not in other stroma cell types. Conclusions NAT can enhance complement production and signaling within the TME, which is associated with reduced immunosuppression in PDAC. These findings suggest that local complement dynamics could serve as a novel biomarker for prognosis, evaluating treatment response and resistance, and guiding therapeutic strategies in NAT-treated PDAC patients.
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Affiliation(s)
- Xiaofei Zhang
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Ruoxin Lan
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA
| | - Yongjun Liu
- Department of Pathology and Laboratory Medicine, University of Wisconsin-Madison, Madison, WI
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA
| | - Venu G Pillarisetty
- Department of Surgery, University of Washington School of Medicine, Seattle, WA
| | - Danting Li
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA
| | - Chaohui L Zhao
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Suparna A. Sarkar
- Department of Pathology and Laboratory Medicine, New York University Grossman School of Medicine, New York, NY
| | - Weiguo Liu
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Iman Hanna
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Mala Gupta
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Cristina Hajdu
- Department of Pathology and Laboratory Medicine, New York University Grossman School of Medicine, New York, NY
| | - Jonathan Melamed
- Department of Pathology and Laboratory Medicine, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Michael Shusterman
- Department of Oncology, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Jessica Widmer
- Department of Gastroenterology, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - John Allendorf
- Department of Surgery, New York University Grossman Long Island School of Medicine, Long Island, NY
| | - Yao-Zhong Liu
- Department of Biostatistics and Data Science, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA
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Olaoba OT, Yang M, Adelusi TI, Maidens T, Kimchi ET, Staveley-O’Carroll KF, Li G. Targeted Therapy for Highly Desmoplastic and Immunosuppressive Tumor Microenvironment of Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:1470. [PMID: 38672552 PMCID: PMC11048089 DOI: 10.3390/cancers16081470] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2024] [Revised: 04/05/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a very poor prognosis. Despite advancements in treatment strategies, PDAC remains recalcitrant to therapies because patients are often diagnosed at an advanced stage. The advanced stage of PDAC is characterized by metastasis, which typically renders it unresectable by surgery or untreatable by chemotherapy. The tumor microenvironment (TME) of PDAC comprises highly proliferative myofibroblast-like cells and hosts the intense deposition of a extracellular matrix component that forms dense fibrous connective tissue, a process called the desmoplastic reaction. In desmoplastic TMEs, the incessant aberration of signaling pathways contributes to immunosuppression by suppressing antitumor immunity. This feature offers a protective barrier that impedes the targeted delivery of drugs. In addition, the efficacy of immunotherapy is compromised because of the immune cold TME of PDAC. Targeted therapy approaches towards stromal and immunosuppressive TMEs are challenging. In this review, we discuss cellular and non-cellular TME components that contain actionable targets for drug development. We also highlight findings from preclinical studies and provide updates about the efficacies of new investigational drugs in clinical trials.
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Affiliation(s)
- Olamide T. Olaoba
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, USA
| | - Ming Yang
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
| | - Temitope I. Adelusi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
| | - Tessa Maidens
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
| | - Eric T. Kimchi
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
| | - Kevin F. Staveley-O’Carroll
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
| | - Guangfu Li
- Department of Surgery, University of Missouri, Columbia, MO 65212, USA; (O.T.O.); (M.Y.); (T.I.A.); (T.M.); (E.T.K.)
- Department of Molecular Microbiology and Immunology, University of Missouri, Columbia, MO 65212, USA
- Roy Blunt NextGen Precision Health Institute, University of Missouri, Columbia, MO 65212, USA
- Harry S. Truman Memorial Veterans’ Hospital, Columbia, MO 65201, USA
- Ellis Fischel Cancer Center, University of Missouri, Columbia, MO 65212, USA
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Pothuri VS, Hogg GD, Conant L, Borcherding N, James CA, Mudd J, Williams G, Seo YD, Hawkins WG, Pillarisetty VG, DeNardo DG, Fields RC. Intratumoral T-cell receptor repertoire composition predicts overall survival in patients with pancreatic ductal adenocarcinoma. Oncoimmunology 2024; 13:2320411. [PMID: 38504847 PMCID: PMC10950267 DOI: 10.1080/2162402x.2024.2320411] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 02/14/2024] [Indexed: 03/21/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is refractory to immune checkpoint inhibitor therapy. However, intratumoral T-cell infiltration correlates with improved overall survival (OS). Herein, we characterized the diversity and antigen specificity of the PDAC T-cell receptor (TCR) repertoire to identify novel immune-relevant biomarkers. Demographic, clinical, and TCR-beta sequencing data were collated from 353 patients across three cohorts that underwent surgical resection for PDAC. TCR diversity was calculated using Shannon Wiener index, Inverse Simpson index, and "True entropy." Patients were clustered by shared repertoire specificity. TCRs predictive of OS were identified and their associated transcriptional states were characterized by single-cell RNAseq. In multivariate Cox regression models controlling for relevant covariates, high intratumoral TCR diversity predicted OS across multiple cohorts. Conversely, in peripheral blood, high abundance of T-cells, but not high diversity, predicted OS. Clustering patients based on TCR specificity revealed a subset of TCRs that predicts OS. Interestingly, these TCR sequences were more likely to encode CD8+ effector memory and CD4+ T-regulatory (Tregs) T-cells, all with the capacity to recognize beta islet-derived autoantigens. As opposed to T-cell abundance, intratumoral TCR diversity was predictive of OS in multiple PDAC cohorts, and a subset of TCRs enriched in high-diversity patients independently correlated with OS. These findings emphasize the importance of evaluating peripheral and intratumoral TCR repertoires as distinct and relevant biomarkers in PDAC.
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Affiliation(s)
- Vikram S. Pothuri
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Graham D. Hogg
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - Leah Conant
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Nicholas Borcherding
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
| | - C. Alston James
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Jacqueline Mudd
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Greg Williams
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
| | - Yongwoo David Seo
- Department of Surgery, University of Washington School of Medicine, Seattle, WA, USA
- Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - William G. Hawkins
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MOUSA
| | - Venu G. Pillarisetty
- Department of Surgery, University of Washington School of Medicine, Seattle, WA, USA
- Fred Hutchinson Cancer Center, Seattle, WAUSA
| | - David G. DeNardo
- Department of Medicine, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MOUSA
| | - Ryan C. Fields
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, MOUSA
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Rezagholizadeh F, Tajik F, Talebi M, Taha SR, Shariat Zadeh M, Farhangnia P, Hosseini HS, Nazari A, Mollazadeh Ghomi S, Kamrani Mousavi SM, Haeri Moghaddam N, Khorramdelazad H, Joghataei MT, Safari E. Unraveling the potential of CD8, CD68, and VISTA as diagnostic and prognostic markers in patients with pancreatic ductal adenocarcinoma. Front Immunol 2024; 15:1283364. [PMID: 38357542 PMCID: PMC10865497 DOI: 10.3389/fimmu.2024.1283364] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 01/15/2024] [Indexed: 02/16/2024] Open
Abstract
Introduction Pancreatic cancer is a truculent disease with limited treatment options and a grim prognosis. Immunotherapy has shown promise in treating various types of cancer, but its effectiveness in pancreatic cancer has been lacking. As a result, it is crucial to identify markers associated with immunological pathways in order to improve the treatment outcomes for this deadly cancer. The purpose of this study was to investigate the diagnostic and prognostic significance of three markers, CD8, CD68, and VISTA, in pancreatic ductal adenocarcinoma (PDAC), the most common subtype of pancreatic cancer. Methods We analyzed gene expression data from Gene Expression Omnibus (GEO) database using bioinformatics tools. We also utilized the STRING online tool and Funrich software to study the protein-protein interactions and transcription factors associated with CD8, CD68, and VISTA. In addition, tissue microarray (TMA) and immunohistochemistry (IHC) staining were performed on 228 samples of PDAC tissue and 10 samples of normal pancreatic tissue to assess the expression levels of the markers. We then correlated these expression levels with the clinicopathological characteristics of the patients and evaluated their survival rates. Results The analysis of the GEO data revealed slightly elevated levels of VISTA in PDAC samples compared to normal tissues. However, there was a significant increase in CD68 expression and a notable reduction in CD8A expression in pancreatic cancer. Further investigation identified potential protein-protein interactions and transcription factors associated with these markers. The IHC staining of PDAC tissue samples showed an increased expression of VISTA, CD68, and CD8A in pancreatic cancer tissues. Moreover, we found correlations between the expression levels of these markers and certain clinicopathological features of the patients. Additionally, the survival analysis revealed that high expression of CD8 was associated with better disease-specific survival and progression-free survival in PDAC patients. Conclusion These findings highlight the potential of CD8, CD68, and VISTA as diagnostic and prognostic indicators in PDAC.
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Affiliation(s)
- Fereshteh Rezagholizadeh
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Tajik
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Morteza Talebi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Human and Animal Cell Bank, Iranian Biological Resource Center (IBRC), Tehran, Iran
| | - Seyed Reza Taha
- Oncopathology Research Center, Iran University of Medical Sciences, Tehran, Iran
| | | | - Pooya Farhangnia
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
| | - Hamideh Sadat Hosseini
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Aram Nazari
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Shabnam Mollazadeh Ghomi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Immunology Board for Transplantation and Cell-Based Therapeutics (ImmunoTACT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
- Department of Pathology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Seyede Mahtab Kamrani Mousavi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Haeri Moghaddam
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Medical Nanotechnology, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Hossein Khorramdelazad
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Taghi Joghataei
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elahe Safari
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
- Immunology Research Center, Institute of Immunology and Infectious Diseases, Iran University of Medical Sciences, Tehran, Iran
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8
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Tay AHM, Cinotti R, Sze NSK, Lundqvist A. Inhibition of ERO1a and IDO1 improves dendritic cell infiltration into pancreatic ductal adenocarcinoma. Front Immunol 2023; 14:1264012. [PMID: 38187398 PMCID: PMC10766682 DOI: 10.3389/fimmu.2023.1264012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2023] [Accepted: 12/11/2023] [Indexed: 01/09/2024] Open
Abstract
Introduction Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and treatment resistant cancers. Due to its desmoplastic and hypoxic nature along with an abundance of myeloid cell infiltration and scarce T cell infiltration, PDAC is considered a cold tumor. Methods Here we sought to investigate myeloid cell infiltration and composition in PDAC spheroids by targeting the hypoxia-associated pathways endoplasmic reticulum oxidoreductase 1 alpha (ERO1a) and indoleamine 2,3-dioxygenase 1 (IDO1). Using MiaPaCa2 spheroids with hypoxic core, we assessed the roles of ERO1a and IDO1 inhibition in modulating monocyte infiltration and differentiation, followed by characterizing immunomodulatory factors secreted using LC-MS/MS. Results Inhibition of ERO1a and IDO1 significantly improved monocyte infiltration and differentiation into dendritic cells. LC-MS/MS analysis of the PDAC spheroid secretome identified downregulation of hypoxia and PDAC pathways, and upregulation of antigen presentation pathways upon inhibition of ERO1a and IDO1. Furthermore, immunomodulatory factors involved in immune infiltration and migration including interleukin-8, lymphocyte cytosolic protein 1, and transgelin-2, were upregulated upon inhibition of ERO1a and IDO1. Discussion Collectively, our results show that inhibition of ERO1a and IDO1 modulates the tumor microenvironment associated with improved monocyte infiltration and differentiation into dendritic cells to potentially influence therapeutic responses in patients with PDAC.
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Affiliation(s)
- Apple Hui Min Tay
- School of Biological Science, Nanyang Technological University, Singapore, Singapore
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Riccardo Cinotti
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Newman Sui Kwan Sze
- School of Biological Science, Nanyang Technological University, Singapore, Singapore
- Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, ON, Canada
| | - Andreas Lundqvist
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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9
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Cheng D, Hu J, Wu X, Wang B, Chen R, Zhao W, Fang C, Ji M. PD-1 blockade combined with gemcitabine plus nab-paclitaxel is superior to chemotherapy alone in the management of unresectable stage III/IV pancreatic cancer: a retrospective real-world study. Front Oncol 2023; 13:1281545. [PMID: 37965469 PMCID: PMC10641475 DOI: 10.3389/fonc.2023.1281545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Accepted: 10/16/2023] [Indexed: 11/16/2023] Open
Abstract
Background Pancreatic cancer (PC) is widely recognized as one of the most malignant forms of cancer worldwide. Monotherapy with immune checkpoint inhibitors (ICI) has shown limited efficacy in treating this disease. There was controversy surrounding whether combining ICI with chemotherapy provided superior outcomes compared to chemotherapy alone. Methods In this study, patients diagnosed with unresectable stage III/IV pancreatic cancer (PC) were classified as receiving programmed cell death protein 1 (PD-1) blockade plus gemcitabine and nab-paclitaxel (AG regimen) (PD-1/chemo, n=27, 50.9%) or chemotherapy alone (chemo, n=26, 49.1%) arm. The primary study endpoints included progression-free survival (PFS) and overall survival (OS), with an additional assessment of treatment-related adverse events graded as three or higher. Chi-square (χ2) statistics were employed to analyze the clinical differences between the two groups, while Kaplan-Meier curves were used to assess the difference in PFS and OS. Statistical significance was defined as P-values less than 0.05 (P < 0.05). Results The median follow-up duration was 22 months (range 1-28 months). In the PD-1/chemo arm, the median PFS was eight months, whereas it was 3.5 months in the chemo arm (HR=0.459, 95% CI: 0.252-0.846, P=0.002). Furthermore, the median OS was 15 months in the PD-1/chemo arm and eight months in the chemo arm (HR=0.345, 95% CI: 0.183-0.653, P<0.001). Within the PD-1/chemo arm, 15 (55.6%) patients experienced grade 3 treatment-related adverse events, compared to 13 (50.0%) patients in the chemo arm. Conclusions PD-1 blockade combined with nab-paclitaxel plus gemcitabine demonstrated superior efficacy to chemotherapy alone for unresectable stage III/IV PC patients. Future studies were warranted to identify immunosensitive patient subgroups within the PC population, ultimately leading to the development of more efficacious therapeutic strategies.
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Affiliation(s)
| | | | | | | | | | | | - Cheng Fang
- Departments of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
| | - Mei Ji
- Departments of Oncology, The Third Affiliated Hospital of Soochow University, Changzhou, China
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10
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Dickerson LK, Carter JA, Kohli K, Pillarisetty VG. Emerging interleukin targets in the tumour microenvironment: implications for the treatment of gastrointestinal tumours. Gut 2023; 72:1592-1606. [PMID: 37258094 DOI: 10.1136/gutjnl-2023-329650] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Accepted: 05/15/2023] [Indexed: 06/02/2023]
Abstract
The effectiveness of antitumour immunity is dependent on intricate cytokine networks. Interleukins (ILs) are important mediators of complex interactions within the tumour microenvironment, including regulation of tumour-infiltrating lymphocyte proliferation, differentiation, migration and activation. Our evolving and increasingly nuanced understanding of the cell type-specific and heterogeneous effects of IL signalling has presented unique opportunities to fine-tune elaborate IL networks and engineer new targeted immunotherapeutics. In this review, we provide a primer for clinicians on the challenges and potential of IL-based treatment. We specifically detail the roles of IL-2, IL-10, IL-12 and IL-15 in shaping the tumour-immune landscape of gastrointestinal malignancies, paying particular attention to promising preclinical findings, early-stage clinical research and innovative therapeutic approaches that may properly place ILs to the forefront of immunotherapy regimens.
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Affiliation(s)
| | - Jason A Carter
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
| | - Karan Kohli
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
- Flatiron Bio, Palo Alto, California, USA
| | - Venu G Pillarisetty
- Hepatopancreatobiliary Surgery, University of Washington, Seattle, Washington, USA
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11
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Yi Q, Wang J, Liu T, Yao Y, Loveless I, Subedi K, Toor J, Adrianto I, Xiao H, Chen B, Crawford HC, Fang D, Zhou L, Mi QS. scRNA-Seq and imaging mass cytometry analyses unveil iNKT cells-mediated anti-tumor immunity in pancreatic cancer liver metastasis. Cancer Lett 2023; 561:216149. [PMID: 36990268 PMCID: PMC11737350 DOI: 10.1016/j.canlet.2023.216149] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/18/2023] [Accepted: 03/24/2023] [Indexed: 03/29/2023]
Abstract
Invariant natural killer T (iNKT) cells are innate-like T cells that are abundant in liver sinusoids and play a critical role in tumor immunity. However, the role of iNKT cells in pancreatic cancer liver metastasis (PCLM) has not been fully explored. In this study, we employed a hemi-spleen pancreatic tumor cell injection mouse model of PCLM, a model that closely mimics clinical conditions in humans, to explore the role of iNKT cells in PCLM. Activation of iNKT cells with α-galactosylceramide (αGC) markedly increased immune cell infiltration and suppressed PCLM progression. Via single cell RNA sequencing (scRNA-seq) we profiled over 30,000 immune cells from normal liver and PCLM with or without αGC treatment and were able to characterize the global changes of the immune cells in the tumor microenvironment upon αGC treatment, identifying a total of 12 subpopulations. Upon treatment with αGC, scRNA-Seq and flow cytometry analyses revealed increased cytotoxic activity of iNKT/NK cells and skewing CD4 T cells towards a cytotoxic Th1 profile and CD8 T cells towards a cytotoxic profile, characterized by higher proliferation and reduced exhaustion marker PD1 expression. Moreover, αGC treatment excluded tumor associated macrophages. Lastly, imaging mass cytometry analysis uncovered the reduced epithelial to mesenchymal transition related markers and increased active CD4 and CD8 T cells in PCLM with αGC treatment. Overall, our findings uncover the protective function of activated iNKT cells in pancreatic cancer liver metastasis through increased NK and T cell immunity and decreased tumor associated macrophages.
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Affiliation(s)
- Qijun Yi
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA
| | - Jie Wang
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA
| | - Tingting Liu
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA
| | - Yi Yao
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA
| | - Ian Loveless
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA; Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, 48202, USA
| | - Kalpana Subedi
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA
| | - Jugmohit Toor
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA
| | - Indra Adrianto
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA; Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, 48202, USA; Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, 48824, USA
| | - Hua Xiao
- Department of Physiology, College of Natural Science, Michigan State University, East Lansing, MI, 48824, USA
| | - Bin Chen
- Department of Pediatrics and Human Development, Michigan State University, Grand Rapids, MI, USA
| | - Howard C Crawford
- Henry Ford Pancreatic Cancer Center, Department of Surgery, Henry Ford Health, Detroit, MI, 48202, USA
| | - Deyu Fang
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Li Zhou
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA; Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, 48202, USA; Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, 48824, USA; Department of Internal Medicine, Henry Ford Health, Detroit, MI, 48202, USA.
| | - Qing-Sheng Mi
- Center for Cutaneous Biology and Immunology, Department of Dermatology, Henry Ford Health, Detroit, MI, 48202, USA; Immunology Research Program, Henry Ford Cancer Institute, Henry Ford Health, Detroit, MI, 48202, USA; Center for Bioinformatics, Department of Public Health Sciences, Henry Ford Health, Detroit, MI, 48202, USA; Department of Medicine, College of Human Medicine, Michigan State University, East Lansing, MI, 48824, USA; Department of Internal Medicine, Henry Ford Health, Detroit, MI, 48202, USA.
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12
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Correlation between hypoxia and HGF/c-MET expression in the management of pancreatic cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188869. [PMID: 36842767 DOI: 10.1016/j.bbcan.2023.188869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Revised: 01/16/2023] [Accepted: 02/07/2023] [Indexed: 02/28/2023]
Abstract
Pancreatic cancer (PC) is very deadly and difficult to treat. The presence of hypoxia has been shown to increase the probability of cancer developing and spreading. Pancreatic ductal adenocarcinoma (PDAC/PC) has traditionally viewed a highly lethal form of cancer due to its high occurrence of early metastases. Desmoplasia/stroma is often thick and collagenous, with pancreatic stellate cells as the primary source (PSCs). Cancer cells and other stromal cells interact with PSCs, promoting disease development. The hepatocyte growth factor (HGF)/c-MET pathway have been proposed as a growth factor mechanism mediating this interaction. Human growth factor (HGF) is secreted by pancreatic stellate cells (PSCs), and its receptor, c-MET, is generated by pancreatic cancer cells and endothelial cells. Hypoxia is frequent in malignant tumors, particularly pancreatic (PC). Hypoxia results from limitless tumor development and promotes survival, progression, and invasion. Hypoxic is becoming a critical driver and therapeutic target of pancreatic cancer as its hypoxia microenvironment is defined. Recent breakthroughs in cancer biology show that hypoxia promotes tumor proliferation, aggressiveness, and therapeutic resistance. Hypoxia-inducible factors (HIFs) stabilize hypoxia signaling. Hypoxia cMet is a key component of pancreatic tumor microenvironments, which also have a fibrotic response, that hypoxia, promotes and modulates. c-Met is a tyrosine-protein kinase. As describe it simply, the MET gene in humans' codes for a protein called hepatocyte growth factor receptor (HGFR). Most cancerous tumors and pancreatic cancer in particular, suffer from a lack of oxygen (PC). Due to unrestrained tumor development, hypoxia develops, actively contributing to tumor survival, progression, and invasion. As the processes by which hypoxia signaling promotes invasion and metastasis become clear, c-MET has emerged as an important determinant of pancreatic cancer malignancy and a potential pharmacological target. This manuscript provides the most current findings on the role of hypoxia and HGF/c-MET expression in the treatment of pancreatic cancer.
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13
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Sinha M, Betts C, Zhang L, Griffith MJ, Solman I, Chen B, Liu E, Tamaki W, Stultz J, Marquez J, Sivagnanam S, Cheung A, Pener D, Fahlman A, Taber E, Lerner K, Crocker M, Todd K, Rajagopalan B, Ware C, Bridge M, Vo J, Dragomanovich H, Sudduth-Klinger J, Vaccaro G, Lopez CD, Tempero M, Coussens LM, Fong L. Modulation of myeloid and T cells in vivo by Bruton's tyrosine kinase inhibitor ibrutinib in patients with metastatic pancreatic ductal adenocarcinoma. J Immunother Cancer 2023; 11:jitc-2022-005425. [PMID: 36593070 PMCID: PMC9809229 DOI: 10.1136/jitc-2022-005425] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/07/2022] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND In preclinical studies of pancreatic ductal adenocarcinoma (PDAC), ibrutinib improved the antitumor efficacy of the standard of care chemotherapy. This led to a phase 1b clinical trial to determine the safety, tolerability, and immunologic effects of ibrutinib treatment in patients with advanced PDAC. METHODS Previously untreated patients with PDAC were enrolled in a phase 1b clinical trial (ClinicalTrials.gov) to determine the safety, toxicity, and maximal tolerated dose of ibrutinib when administered with the standard regimen of gemcitabine and nab-paclitaxel. To study the immune response to ibrutinib alone, the trial included an immune response arm where patients were administered with ibrutinib daily for a week followed by ibrutinib combined with gemcitabine and nab-paclitaxel. Endoscopic ultrasonography-guided primary PDAC tumor biopsies and blood were collected before and after ibrutinib monotherapy. Changes in abundance and functional state of immune cells in the blood was evaluated by mass cytometry by time of flight and statistical scaffold analysis, while that in the local tumor microenvironment (TME) were assessed by multiplex immunohistochemistry. Changes in B-cell receptor and T-cell receptor repertoire were assessed by sequencing and analysis of clonality. RESULTS In the blood, ibrutinib monotherapy significantly increased the frequencies of activated inducible T cell costimulator+(ICOS+) CD4+ T cells and monocytes. Within the TME, ibrutinib monotherapy led to a trend in decreased B-cell abundance but increased interleukin-10+ B-cell frequency. Monotherapy also led to a trend in increased mature CD208+dendritic cell density, increased late effector (programmed cell death protein 1 (PD-1-) eomesodermin (EOMES+)) CD8+ T-cell frequency, with a concomitantly decreased dysfunctional (PD-1+ EOMES+) CD8+ T-cell frequency. When ibrutinib was combined with chemotherapy, most of these immune changes were not observed. Patients with partial clinical responses had more diverse T and B cell receptor repertoires prior to therapy initiation. CONCLUSION Ibrutinib monotherapy skewed the immune landscape both in the circulation and TME towards activated T cells, monocytes and DCs. These effects were not observed when combining ibrutinib with standard of care chemotherapy. Future studies may focus on other therapeutic combinations that augment the immunomodulatory effects of ibrutinib in solid tumors. TRIAL REGISTRATION NUMBER NCT02562898.
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Affiliation(s)
- Meenal Sinha
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Courtney Betts
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Li Zhang
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA,Department of Biostatistics, University of California, San Francisco, California, USA
| | - Madeline J Griffith
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | | | - Brandon Chen
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Eric Liu
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Whitney Tamaki
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Jacob Stultz
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Jaqueline Marquez
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Shamilene Sivagnanam
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Alexander Cheung
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Denise Pener
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Anne Fahlman
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Erin Taber
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Kimberly Lerner
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Matthew Crocker
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Kendra Todd
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Brindha Rajagopalan
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Clarisha Ware
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Mark Bridge
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Johnson Vo
- Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Hannah Dragomanovich
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Julie Sudduth-Klinger
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Gina Vaccaro
- Medical Oncology, Providence Portland Medical Center, Portland, Oregon, USA
| | - Charles D Lopez
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA,Department of Medicine, Oregon Health & Science University, Portland, Oregon, USA
| | - Margaret Tempero
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA
| | - Lisa M Coussens
- Department of Cell, Developmental & Cancer Biology, Oregon Health & Science University, Portland, Oregon, USA
| | - Lawrence Fong
- Division of Hematology/Oncology, Department of Medicine, University of California, San Francisco, California, USA,Parker Institute for Cancer Immunotherapy, San Francisco, California, USA
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14
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Costa AD, Väyrynen SA, Chawla A, Zhang J, Väyrynen JP, Lau MC, Williams HL, Yuan C, Morales-Oyarvide V, Elganainy D, Singh H, Cleary JM, Perez K, Ng K, Freed-Pastor W, Mancias JD, Dougan SK, Wang J, Rubinson DA, Dunne RF, Kozak MM, Brais L, Reilly E, Clancy T, Linehan DC, Chang DT, Hezel AF, Koong AC, Aguirre A, Wolpin BM, Nowak JA. Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer. Clin Cancer Res 2022; 28:5167-5179. [PMID: 36129461 PMCID: PMC9999119 DOI: 10.1158/1078-0432.ccr-22-1125] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 07/01/2022] [Accepted: 09/16/2022] [Indexed: 01/28/2023]
Abstract
PURPOSE Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood. EXPERIMENTAL DESIGN We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes. RESULTS In the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 72% showed a T cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy, and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival. CONCLUSIONS Neoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment toward an anti-tumorigenic state associated with improved patient survival.
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Affiliation(s)
- Andressa Dias Costa
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Sara A. Väyrynen
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Akhil Chawla
- Department of Surgery, Northwestern Medicine Regional Medical Group, Northwestern University Feinberg School of Medicine, Chicago, IL
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL
| | - Jinming Zhang
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Juha P. Väyrynen
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
- Cancer and Translational Medicine Research Unit, Medical Research Center Oulu, Oulu University Hospital, and University of Oulu, Oulu, Finland
| | - Mai Chan Lau
- Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Hannah L. Williams
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Vicente Morales-Oyarvide
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Dalia Elganainy
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Harshabad Singh
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - James M. Cleary
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Kimberly Perez
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Kimmie Ng
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - William Freed-Pastor
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Joseph D. Mancias
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA
| | - Stephanie K. Dougan
- Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Jiping Wang
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Douglas A. Rubinson
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Richard F. Dunne
- Division of Hematology and Oncology, Department of Medicine, Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY
| | - Margaret M. Kozak
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA
| | - Lauren Brais
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Emma Reilly
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Thomas Clancy
- Department of Surgery, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - David C. Linehan
- Department of General Surgery, University of Rochester Medical Center, Rochester, NY
| | - Daniel T. Chang
- Department of Radiation Oncology, Stanford Cancer Institute, Stanford, CA
| | - Aram F. Hezel
- Department of Cell, Developmental & Cancer Biology, Oregon Health and Science University, Portland, OR
| | - Albert C. Koong
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Andrew Aguirre
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
- Broad Institute of MIT and Harvard, Cambridge, MA
| | - Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA
| | - Jonathan A. Nowak
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
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15
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Heiduk M, Plesca I, Glück J, Müller L, Digomann D, Reiche C, von Renesse J, Decker R, Kahlert C, Sommer U, Aust DE, Schmitz M, Weitz J, Seifert L, Seifert AM. Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer. JCI Insight 2022; 7:152761. [PMID: 36509285 DOI: 10.1172/jci.insight.152761] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Accepted: 10/12/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUNDPancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis. At diagnosis, only 20% of patients with PDAC are eligible for primary resection. Neoadjuvant chemotherapy can enable surgical resection in 30%-40% of patients with locally advanced and borderline resectable PDAC. The effects of neoadjuvant chemotherapy on the cytokine production of tumor-infiltrating T cells are unknown in PDAC.METHODSWe performed multiplex immunofluorescence to investigate T cell infiltration in 91 patients with PDAC. Using flow cytometry, we analyzed tumor and matched blood samples from 71 patients with PDAC and determined the frequencies of T cell subsets and their cytokine profiles. Both cohorts included patients who underwent primary resection and patients who received neoadjuvant chemotherapy followed by surgical resection.RESULTSIn human PDAC, T cells were particularly enriched within the tumor stroma. Neoadjuvant chemotherapy markedly enhanced T cell density within the ductal area of the tumor. Whereas infiltration of cytotoxic CD8+ T cells was unaffected by neoadjuvant chemotherapy, the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced in the pancreatic tumor microenvironment after neoadjuvant treatment. Moreover, neoadjuvant chemotherapy increased the production of proinflammatory cytokines by tumor-infiltrating T cells, with enhanced TNF-α and IL-2 and reduced IL-4 and IL-10 expression.CONCLUSIONNeoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile. Combinational treatment strategies incorporating immunotherapy in neoadjuvant regimens may unleash more effective antitumor responses and improve prognosis of pancreatic cancer.FUNDINGThis work was supported by the Jung Foundation for Science and Research, the Monika Kutzner Foundation, the German Research Foundation (SE2980/5-1), the German Cancer Consortium, and the Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden.
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Affiliation(s)
- Max Heiduk
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany
| | - Ioana Plesca
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Jessica Glück
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Luise Müller
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - David Digomann
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Charlotte Reiche
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Janusz von Renesse
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Rahel Decker
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Christoph Kahlert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Ulrich Sommer
- Institute of Pathology, Faculty of Medicine Carl Gustav Carus, and
| | - Daniela E Aust
- Institute of Pathology, Faculty of Medicine Carl Gustav Carus, and.,National Center for Tumor Diseases, Biobank Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Marc Schmitz
- National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,Institute of Immunology, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Lena Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
| | - Adrian M Seifert
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,National Center for Tumor Diseases, Dresden, Germany; German Cancer Research Center, Heidelberg, Germany; Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; and Helmholtz-Zentrum Dresden-Rossendorf, Dresden, Germany.,German Cancer Consortium, Partner Site Dresden, German Cancer Research Center, Heidelberg, Germany
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16
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Bockorny B, Grossman JE, Hidalgo M. Facts and Hopes in Immunotherapy of Pancreatic Cancer. Clin Cancer Res 2022; 28:4606-4617. [PMID: 35775964 DOI: 10.1158/1078-0432.ccr-21-3452] [Citation(s) in RCA: 44] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 04/26/2022] [Accepted: 06/14/2022] [Indexed: 01/24/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most challenging cancers to treat. For patients with advanced and metastatic disease, chemotherapy has yielded only modest incremental benefits, which are not durable. Immunotherapy has revolutionized the treatment of other solid tumors by leading to cures where none existed only a decade ago, yet it has made few inroads with PDAC. A host of trials with promising preclinical data have failed, except for in a small minority of patients with selected biomarkers. There is, however, a glimmer of hope, which we seek to cultivate. In this review, we discuss recent advances in the understanding of the uniquely immunosuppressive tumor microenvironment (TME) in PDAC, learnings from completed trials of checkpoint inhibitors, TME modifiers, cellular and vaccine therapies, oncolytic viruses, and other novel approaches. We go on to discuss our expectations for improved preclinical models of immunotherapy in PDAC, new approaches to modifying the TME including the myeloid compartment, and emerging biomarkers to better select patients who may benefit from immunotherapy. We also discuss improvements in clinical trial design specific to immunotherapy that will help us better measure success when we find it. Finally, we discuss the urgent imperative to better design and execute bold, but rational, combination trials of novel agents designed to cure patients with PDAC.
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Affiliation(s)
- Bruno Bockorny
- Division of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
- Harvard Medical School, Boston, Massachusetts
| | | | - Manuel Hidalgo
- Division of Hematology and Medical Oncology, Weill Cornell Medical College, New York, New York
- New York-Presbyterian Hospital, New York, New York
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17
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Zhang H, Ye L, Yu X, Jin K, Wu W. Neoadjuvant therapy alters the immune microenvironment in pancreatic cancer. Front Immunol 2022; 13:956984. [PMID: 36225934 PMCID: PMC9548645 DOI: 10.3389/fimmu.2022.956984] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Accepted: 09/08/2022] [Indexed: 11/13/2022] Open
Abstract
Pancreatic cancer has an exclusive inhibitory tumor microenvironment characterized by a dense mechanical barrier, profound infiltration of immunosuppressive cells, and a lack of penetration of effector T cells, which constitute an important cause for recurrence and metastasis, resistance to chemotherapy, and insensitivity to immunotherapy. Neoadjuvant therapy has been widely used in clinical practice due to its many benefits, including the ability to improve the R0 resection rate, eliminate tumor cell micrometastases, and identify highly malignant tumors that may not benefit from surgery. In this review, we summarize multiple aspects of the effect of neoadjuvant therapy on the immune microenvironment of pancreatic cancer, discuss possible mechanisms by which these changes occur, and generalize the theoretical basis of neoadjuvant chemoradiotherapy combined with immunotherapy, providing support for the development of more effective combination therapeutic strategies to induce potent immune responses to tumors.
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Affiliation(s)
- Huiru Zhang
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Longyun Ye
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Weiding Wu
- Department of Pancreatic Surgery, Shanghai Cancer Centre, Fudan University, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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18
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Bakhshwin A, Allende DS. The Histopathology of Neoadjuvant-Treated (NAT) Pancreatic Ductal Adenocarcinoma. Surg Pathol Clin 2022; 15:511-528. [PMID: 36049833 DOI: 10.1016/j.path.2022.05.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Examination of pancreatic ductal adenocarcinoma after NAT with the intent of diagnosis and outcome prediction remains a challenging task. The lack of a uniform approach to macroscopically assess these cases along with variations in sampling adds to the complexity. Several TRG systems have been proposed to correlate with an overall survival. In clinical practice, most of these TRG schemes have shown low level of interobserver agreement arguing for a need of larger studies and more innovative ways to assess outcome in this population.
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Affiliation(s)
- Ahmed Bakhshwin
- Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L1-360-R11, Cleveland, OH 44195, USA. https://twitter.com/Ahmed_Bakhshwin
| | - Daniela S Allende
- Robert J. Tomsich Pathology & Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L25, Cleveland, OH 44195, USA.
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19
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Gössling GCL, Zhen DB, Pillarisetty VG, Chiorean EG. Combination immunotherapy for pancreatic cancer: challenges and future considerations. Expert Rev Clin Immunol 2022; 18:1173-1186. [PMID: 36045547 DOI: 10.1080/1744666x.2022.2120471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION : Immune checkpoint inhibitors (ICI) have not yielded significant efficacy in pancreatic ductal adenocarcinoma (PDA), despite the role of the innate and adaptive immune systems on progression and survival. However, recently identified pathways have identified new targets and generated promising clinical investigations into promoting an effective immune-mediated antitumor response in PDA. AREAS COVERED : We review biological mechanisms associated with immunotherapy resistance and outline strategies for therapeutic combinations with established and novel therapies in PDA. EXPERT OPINION : Pancreatic cancers rarely benefits from treatment with ICI due to an immunosuppressive tumor microenvironment (TME). New understandings of factors associated with the suppressive TME, include low and poor quality neoantigens, constrained effector T cells infiltration, and the presence of a dense, suppressive myeloid cell population. These findings have been translated into new clinical investigations evaluating novel therapies in combination with ICI and/or standard systemic chemotherapy and radiotherapy. The epithelial, immune, and stromal compartments are intricately related in PDA, and the framework for successful targeting of this disease requires a comprehensive and personalized approach.
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Affiliation(s)
| | - David B Zhen
- University of Washington School of Medicine, Seattle, WA, USA.,Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Venu G Pillarisetty
- University of Washington School of Medicine, Seattle, WA, USA.,Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - E Gabriela Chiorean
- University of Washington School of Medicine, Seattle, WA, USA.,Fred Hutchinson Cancer Center, Seattle, WA, USA
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20
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Nucleolin Therapeutic Targeting Decreases Pancreatic Cancer Immunosuppression. Cancers (Basel) 2022; 14:cancers14174265. [PMID: 36077801 PMCID: PMC9454580 DOI: 10.3390/cancers14174265] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/01/2022] [Accepted: 08/26/2022] [Indexed: 12/24/2022] Open
Abstract
Background: The pancreatic ductal adenocarcinoma (PDAC) microenvironment is highly fibrotic and hypoxic, with poor immune cell infiltration. Recently, we showed that nucleolin (NCL) inhibition normalizes tumour vessels and impairs PDAC growth. Methods: Immunocompetent mouse models of PDAC were treated by the pseudopeptide N6L, which selectively inhibits NCL. Tumour-infiltrating immune cells and changes in the tumour microenvironment were analysed. Results: N6L reduced the proportion of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) and increased tumour-infiltrated T lymphocytes (TILs) with an activated phenotype. Low-dose anti-VEGFR2 treatment normalized PDAC vessels but did not modulate the immune suppressive microenvironment. RNAseq analysis of N6L-treated PDAC tumours revealed a reduction of cancer-associated fibroblast (CAF) expansion in vivo and in vitro. Notably, N6L treatment decreased IL-6 levels both in tumour tissues and in serum. Treating mPDAC by an antibody blocking IL-6 reduced the proportion of Tregs and MDSCs and increased the amount of TILs, thus mimicking the effects of N6L. Conclusions: These results demonstrate that NCL inhibition blocks the amplification of lymphoid and myeloid immunosuppressive cells and promotes T cell activation in PDAC through a new mechanism of action dependent on the direct inhibition of the tumoral stroma.
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21
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Wang H, Chen L, Qi L, Jiang N, Zhang Z, Guo H, Song T, Li J, Li H, Zhang N, Chen R. A Single-Cell Atlas of Tumor-Infiltrating Immune Cells in Pancreatic Ductal Adenocarcinoma. Mol Cell Proteomics 2022; 21:100258. [PMID: 35718340 PMCID: PMC9294203 DOI: 10.1016/j.mcpro.2022.100258] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 06/09/2022] [Accepted: 06/11/2022] [Indexed: 11/30/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited treatment options. To guide the design of more effective immunotherapy strategies, mass cytometry was employed to characterize the cellular composition of the PDAC-infiltrating immune cells. The expression of 33 protein markers was examined at the single-cell level in more than two million immune cells from four types of clinical samples, including PDAC tumors, normal pancreatic tissues, chronic pancreatitis tissues, and peripheral blood. Based on the analyses, we identified 23 distinct T-cell phenotypes, with some cell clusters exhibiting aberrant frequencies in the tumors. Programmed cell death protein 1 (PD-1) was extensively expressed in CD4+ and CD8+ T cells and coexpressed with both stimulatory and inhibitory immune markers. In addition, we observed elevated levels of functional markers, such as CD137L and CD69, in PDAC-infiltrating immune cells. Moreover, the combination of PD-1 and CD8 was used to stratify PDAC tumors from The Cancer Genome Atlas database into three immune subtypes, with S1 (PD-1+CD8+) exhibiting the best prognosis. Further analysis suggested distinct molecular mechanisms for immune exclusion in different subtypes. Taken together, the single-cell protein expression data depicted a detailed cell atlas of the PDAC-infiltrating immune cells and revealed clinically relevant information regarding useful cell phenotypes and targets for immunotherapy development.
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Affiliation(s)
- Hao Wang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China; Department of Clinical Laboratory, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Lu Chen
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Lisha Qi
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Na Jiang
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China
| | - Zhibin Zhang
- Department of General Surgery, Tianjin First Central Hospital, Tianjin, China
| | - Hua Guo
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Tianqiang Song
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China
| | - Jun Li
- Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Hongle Li
- Department of Molecular Pathology, Clinical Pathology Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China
| | - Ning Zhang
- Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University, Tianjin, China; Peking University First Hospital, Peking University Health Science Center, Beijing, China.
| | - Ruibing Chen
- School of Pharmaceutical Science and Technology, Tianjin University, Tianjin, China.
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22
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Nurmi AM, Hagström J, Mustonen H, Seppänen H, Haglund C. The expression and prognostic value of toll-like receptors (TLRs) in pancreatic cancer patients treated with neoadjuvant therapy. PLoS One 2022; 17:e0267792. [PMID: 35536778 PMCID: PMC9089880 DOI: 10.1371/journal.pone.0267792] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 04/15/2022] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVES Toll-like receptors (TLRs) play a pivotal role in the immune system and carcinogenesis. There is no research on TLR expression and association with survival among preoperatively treated pancreatic cancer patients. We studied the expression intensity and prognostic value of TLRs in pancreatic cancer patients treated with neoadjuvant therapy (NAT) and compared the results to patients undergoing upfront surgery (US). METHOD Between 2000 and 2015, 71 borderline resectable patients were treated with NAT and surgery and 145 resectable patients underwent upfront surgery at Helsinki University Hospital, Finland. We immunostained TLRs 1-5, 7, and 9 on sections of tissue-microarray. We classified TLR expression as 0 (negative), 1 (mild), 2 (moderate), or 3 (strong) and divided into high (2-3) and low (0-1) expression for statistical purposes. RESULTS Among TLRs 1, 3, and 9 (TLR1 81% vs 70%, p = 0.008; TLR3 92% vs 68%, p = 0.001; TLR9 cytoplasmic 83% vs 42%, p<0.001; TLR9 membranous 53% vs 25%, p = 0.002) NAT patients exhibited a higher immunopositivity score more frequently than patients undergoing upfront surgery. Among NAT patients, a high expression of TLR1 [Hazards ratio (HR) 0.48, p<0.05] associated with a longer postoperative survival, whereas among US patients, high expression of TLR5 (HR 0.64, p<0.05), TLR7 (HR 0.59, p<0.01, and both TLR7 and TLR9 (HR 0.5, p<0.01) predicted a favorable postoperative outcome in separate analysis adjusted for background variables. CONCLUSIONS We found higher immunopositive intensities among TLRs 1, 3, and 9 in NAT patients. A high TLR1 expression associated with a longer survival among NAT patients, however, among US patients, high expression intensity of TLR5 and TLR7 predicted a favorable postoperative outcome in the adjusted analysis.
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Affiliation(s)
- Anna Maria Nurmi
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Jaana Hagström
- Department of Pathology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Department of Oral Pathology and Radiology, University of Turku, Turku, Finland
| | - Harri Mustonen
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Hanna Seppänen
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
- Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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23
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Gartrell RD, Enzler T, Kim PS, Fullerton BT, Fazlollahi L, Chen AX, Minns HE, Perni S, Weisberg SP, Rizk EM, Wang S, Oh EJ, Guo XV, Chiuzan C, Manji GA, Bates SE, Chabot J, Schrope B, Kluger M, Emond J, Rabadán R, Farber D, Remotti HE, Horowitz DP, Saenger YM. Neoadjuvant chemoradiation alters the immune microenvironment in pancreatic ductal adenocarcinoma. Oncoimmunology 2022; 11:2066767. [PMID: 35558160 PMCID: PMC9090285 DOI: 10.1080/2162402x.2022.2066767] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 01/21/2023] Open
Abstract
Patients with pancreatic ductal adenocarcinoma (PDAC) have a grim prognosis despite complete surgical resection and intense systemic therapies. While immunotherapies have been beneficial with many different types of solid tumors, they have almost uniformly failed in the treatment of PDAC. Understanding how therapies affect the tumor immune microenvironment (TIME) can provide insights for the development of strategies to treat PDAC. We used quantitative multiplexed immunofluorescence (qmIF) quantitative spatial analysis (qSA), and immunogenomic (IG) analysis to analyze formalin-fixed paraffin embedded (FFPE) primary tumor specimens from 44 patients with PDAC including 18 treated with neoadjuvant chemoradiation (CRT) and 26 patients receiving no treatment (NT) and compared them with tissues from 40 treatment-naïve melanoma patients. We find that relative to NT tumors, CD3+ T cell infiltration was increased in CRT treated tumors (p = .0006), including increases in CD3+CD8+ cytotoxic T cells (CTLs, p = .0079), CD3+CD4+FOXP3- T helper cells (Th, p = .0010), and CD3+CD4+FOXP3+ regulatory T cells (Tregs, p = .0089) with no difference in CD68+ macrophages. IG analysis from micro-dissected tissues indicated overexpression of genes involved in antigen presentation, T cell activation, and inflammation in CRT treated tumors. Among treated patients, a higher ratio of Tregs to total T cells was associated with shorter survival time (p = .0121). Despite comparable levels of infiltrating T cells in CRT PDACs to melanoma, PDACs displayed distinct spatial profiles with less T cell clustering as defined by nearest neighbor analysis (p < .001). These findings demonstrate that, while CRT can achieve high T cell densities in PDAC compared to melanoma, phenotype and spatial organization of T cells may limit benefit of T cell infiltration in this immunotherapy-resistant tumor.
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Affiliation(s)
- Robyn D. Gartrell
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Thomas Enzler
- Rogel Cancer Center, University of Michigan Medicine, Ann Arbor, MI, USA
| | - Pan S. Kim
- Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Benjamin T. Fullerton
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Ladan Fazlollahi
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - Andrew X. Chen
- Vagelos College of Physicians and Surgeons, Columbia University, New York, NY, USA
| | - Hanna E. Minns
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
| | - Subha Perni
- Harvard Radiation Oncology Program, Massachusetts General Hospital and Brigham and Women’s Hospital/Dana-Farber Cancer Institute, Boston, MA, USA
| | - Stuart P. Weisberg
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - Emanuelle M. Rizk
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Samuel Wang
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Eun Jeong Oh
- Mailman School of Public Health, Columbia University, New York, NY, USA
| | - Xinzheng V. Guo
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Codruta Chiuzan
- Department of Biostatistics, Columbia University Irving Medical Center, New York, NY, USA
| | - Gulam A. Manji
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - Susan E. Bates
- Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
| | - John Chabot
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Beth Schrope
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Michael Kluger
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Jean Emond
- Department of Surgery, Columbia University Irving Medical Center, New York, NY, USA
| | - Raul Rabadán
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
| | - Donna Farber
- Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA
| | - Helen E. Remotti
- Department of Pathology, Columbia University Irving Medical Center, New York, NY, USA
| | - David P. Horowitz
- Department of Radiation Oncology, Columbia University Irving Medical Center, New York, NY, USA
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24
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Merz V, Mangiameli D, Zecchetto C, Quinzii A, Pietrobono S, Messina C, Casalino S, Gaule M, Pesoni C, Vitale P, Trentin C, Frisinghelli M, Caffo O, Melisi D. Predictive Biomarkers for a Personalized Approach in Resectable Pancreatic Cancer. Front Surg 2022; 9:866173. [PMID: 35599791 PMCID: PMC9114435 DOI: 10.3389/fsurg.2022.866173] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 03/25/2022] [Indexed: 12/15/2022] Open
Abstract
The mainstay treatment for patients with immediate resectable pancreatic cancer remains upfront surgery, which represents the only potentially curative strategy. Nevertheless, the majority of patients surgically resected for pancreatic cancer experiences disease relapse, even when a combination adjuvant therapy is offered. Therefore, aiming at improving disease free survival and overall survival of these patients, there is an increasing interest in evaluating the activity and efficacy of neoadjuvant and perioperative treatments. In this view, it is of utmost importance to find biomarkers able to select patients who may benefit from a preoperative therapy rather than upfront surgical resection. Defined genomic alterations and a dynamic inflammatory microenvironment are the major culprits for disease recurrence and resistance to chemotherapeutic treatments in pancreatic cancer patients. Signal transduction pathways or tumor immune microenvironment could predict early recurrence and response to chemotherapy. In the last decade, distinct molecular subtypes of pancreatic cancer have been described, laying the bases to a tailored therapeutic approach, started firstly in the treatment of advanced disease. Patients with homologous repair deficiency, in particular with mutant germline BRCA genes, represent the first subgroup demonstrating to benefit from specific therapies. A fraction of patients with pancreatic cancer could take advantage of genome sequencing with the aim of identifying possible targetable mutations. These genomic driven strategies could be even more relevant in a potentially curative setting. In this review, we outline putative predictive markers that could help in the next future in tailoring the best therapeutic strategy for pancreatic cancer patients with a potentially curable disease.
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Affiliation(s)
- Valeria Merz
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | - Domenico Mangiameli
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | - Camilla Zecchetto
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Alberto Quinzii
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Silvia Pietrobono
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
| | | | - Simona Casalino
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Marina Gaule
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Camilla Pesoni
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | | | - Chiara Trentin
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
| | | | - Orazio Caffo
- Medical Oncology Unit, Santa Chiara Hospital, Trento, Italy
| | - Davide Melisi
- Digestive Molecular Clinical Oncology Research Unit, Università degli Studi di Verona, Verona, Italy
- Investigational Cancer Therapeutics Clinical Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
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25
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Nel AE, Mei KC, Liao YP, Lu X. Multifunctional Lipid Bilayer Nanocarriers for Cancer Immunotherapy in Heterogeneous Tumor Microenvironments, Combining Immunogenic Cell Death Stimuli with Immune Modulatory Drugs. ACS NANO 2022; 16:5184-5232. [PMID: 35348320 PMCID: PMC9519818 DOI: 10.1021/acsnano.2c01252] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
In addition to the contribution of cancer cells, the solid tumor microenvironment (TME) has a critical role in determining tumor expansion, antitumor immunity, and the response to immunotherapy. Understanding the details of the complex interplay between cancer cells and components of the TME provides an unprecedented opportunity to explore combination therapy for intervening in the immune landscape to improve immunotherapy outcome. One approach is the introduction of multifunctional nanocarriers, capable of delivering drug combinations that provide immunogenic stimuli for improvement of tumor antigen presentation, contemporaneous with the delivery of coformulated drug or synthetic molecules that provide immune danger signals or interfere in immune-escape, immune-suppressive, and T-cell exclusion pathways. This forward-looking review will discuss the use of lipid-bilayer-encapsulated liposomes and mesoporous silica nanoparticles for combination immunotherapy of the heterogeneous immune landscapes in pancreatic ductal adenocarcinoma and triple-negative breast cancer. We describe how the combination of remote drug loading and lipid bilayer encapsulation is used for the synthesis of synergistic drug combinations that induce immunogenic cell death, interfere in the PD-1/PD-L1 axis, inhibit the indoleamine-pyrrole 2,3-dioxygenase (IDO-1) immune metabolic pathway, restore spatial access to activated T-cells to the cancer site, or reduce the impact of immunosuppressive stromal components. We show how an integration of current knowledge and future discovery can be used for a rational approach to nanoenabled cancer immunotherapy.
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Affiliation(s)
- André E. Nel
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
- Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, United States
| | - Kuo-Ching Mei
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Yu-Pei Liao
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
| | - Xiangsheng Lu
- Division of NanoMedicine, Department of Medicine, David Geffen School of Medicine University of California, Los Angeles, California, 90095, United States
- California NanoSystems Institute, University of California, Los Angeles, California 90095, United States
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Plesca I, Benešová I, Beer C, Sommer U, Müller L, Wehner R, Heiduk M, Aust D, Baretton G, Bachmann MP, Feldmann A, Weitz J, Seifert L, Seifert AM, Schmitz M. Clinical Significance of Tumor-Infiltrating Conventional and Plasmacytoid Dendritic Cells in Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2022; 14:cancers14051216. [PMID: 35267524 PMCID: PMC8909898 DOI: 10.3390/cancers14051216] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/18/2022] [Accepted: 02/22/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The tumor immune contexture plays a pivotal role for the clinical outcome of cancer patients and the efficacy of various treatment modalities. Dendritic cells (DCs) represent a major component of the tumor immune architecture that can either efficiently promote antitumor immunity or contribute to immunosuppression. Here, we investigated the frequency, spatial organization, and clinical significance of tumor-infiltrating conventional DCs type 1 (cDC1s) and type 2 (cDC2s) and plasmacytoid DCs (pDCs) in pancreatic ductal adenocarcinoma (PDAC). A higher frequency of whole tumor area (WTA)- and tumor stroma (TS)-infiltrating cDC1s, and of intraepithelial tumor-infiltrating cDC2s, was significantly associated with improved survival. Furthermore, a higher density of both WTA- and TS-infiltrating cDC1s and pDCs emerged as an independent prognostic factor for better survival. These results provide evidence that tumor-infiltrating DCs are associated with survival of PDAC patients and may support the design of novel DC-based immunotherapeutic strategies. Abstract Dendritic cells (DCs) play a key role in the orchestration of antitumor immunity. Activated DCs efficiently enhance antitumor effects mediated by natural killer cells and T lymphocytes. Conversely, tolerogenic DCs essentially contribute to an immunosuppressive tumor microenvironment. Thus, DCs can profoundly influence tumor progression and clinical outcome of tumor patients. To gain novel insights into the role of human DCs in pancreatic ductal adenocarcinoma (PDAC), we explored the frequency, spatial organization, and clinical significance of conventional DCs type 1 (cDC1s) and type 2 (cDC2s) and plasmacytoid DCs (pDCs) in primary PDAC tissues. A higher density of whole tumor area (WTA)- and tumor stroma (TS)-infiltrating cDC1s was significantly associated with better disease-free survival (DFS). In addition, an increased frequency of intraepithelial tumor-infiltrating cDC2s was linked to better DFS and overall survival (OS). Furthermore, an increased density of WTA- and TS-infiltrating pDCs tended to improve DFS. Moreover, a higher frequency of WTA- and TS-infiltrating cDC1s and pDCs emerged as an independent prognostic factor for better DFS and OS. These findings indicate that tumor-infiltrating DCs can significantly influence the clinical outcome of PDAC patients and may contribute to the design of novel treatment options that target PDAC-infiltrating DCs.
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Affiliation(s)
- Ioana Plesca
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (I.P.); (I.B.); (C.B.); (L.M.); (R.W.)
| | - Iva Benešová
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (I.P.); (I.B.); (C.B.); (L.M.); (R.W.)
| | - Carolin Beer
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (I.P.); (I.B.); (C.B.); (L.M.); (R.W.)
| | - Ulrich Sommer
- Institute of Pathology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (U.S.); (D.A.); (G.B.)
| | - Luise Müller
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (I.P.); (I.B.); (C.B.); (L.M.); (R.W.)
| | - Rebekka Wehner
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (I.P.); (I.B.); (C.B.); (L.M.); (R.W.)
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Max Heiduk
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Daniela Aust
- Institute of Pathology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (U.S.); (D.A.); (G.B.)
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Gustavo Baretton
- Institute of Pathology, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (U.S.); (D.A.); (G.B.)
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
| | - Michael P Bachmann
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Tumor Immunology, University Cancer Center (UCC), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
- Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz Center Dresden-Rossendorf, Bautzener Straße 400, 01328 Dresden, Germany;
| | - Anja Feldmann
- Department of Radioimmunology, Institute of Radiopharmaceutical Cancer Research, Helmholtz Center Dresden-Rossendorf, Bautzener Straße 400, 01328 Dresden, Germany;
| | - Jürgen Weitz
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Lena Seifert
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Adrian M Seifert
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Department of Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany
| | - Marc Schmitz
- Institute of Immunology, Faculty of Medicine Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (I.P.); (I.B.); (C.B.); (L.M.); (R.W.)
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, Fetscherstraße 74, 01307 Dresden, Germany; (M.H.); (M.P.B.); (J.W.); (L.S.); (A.M.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany
- Correspondence: ; Tel.: +49-351-458-6501
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Lin YN, Schmidt MO, Sharif GM, Vietsch EE, Kiliti AJ, Barefoot ME, Riegel AT, Wellstein A. Impaired CXCL12 signaling contributes to resistance of pancreatic cancer subpopulations to T cell-mediated cytotoxicity. Oncoimmunology 2022; 11:2027136. [PMID: 35127250 PMCID: PMC8816404 DOI: 10.1080/2162402x.2022.2027136] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/16/2021] [Accepted: 12/16/2021] [Indexed: 11/18/2022] Open
Abstract
Pancreatic cancer remains largely unresponsive to immune modulatory therapy attributable in part to an immunosuppressive, desmoplastic tumor microenvironment. Here, we analyze mechanisms of cancer cell-autonomous resistance to T cells. We used a 3D co-culture model of cancer cell spheroids from the KPC (LSL-KrasG12D/+ /LSL-Trp53R172H/+ /p48-Cre) pancreatic ductal adenocarcinoma (PDAC) model, to examine interactions with tumor-educated T cells isolated from draining lymph nodes of PDAC-bearing mice. Subpopulations of cancer cells resistant to these tumor-educated T cells were isolated from the in vitro co-culture and their properties compared with sensitive cancer cells. In co-culture with resistant cancer cell subpopulations, tumor-educated T cells showed reduced effector T cell functionality, reduced infiltration into tumor cell spheroids and decreased induction of apoptosis. A combination of comparative transcriptomic analyses, cytometric and immunohistochemistry techniques allowed us to dissect the role of differential gene expression and signaling pathways between sensitive and resistant cells. A decreased expression of the chemokine CXCL12 (SDF-1) was revealed as a common feature in the resistant cell subpopulations. Adding back CXCL12 reversed the resistant phenotype and was inhibited by the CXCR4 inhibitor AMD3100 (plerixafor). We conclude that reduced CXCL12 signaling contributes to PDAC subpopulation resistance to T cell-mediated attack.
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Affiliation(s)
- Yuan-Na Lin
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Marcel O. Schmidt
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Ghada M. Sharif
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Eveline E. Vietsch
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
- Department of Surgery, Erasmus Mc, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Amber J. Kiliti
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Megan E. Barefoot
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Anna T. Riegel
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
| | - Anton Wellstein
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
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Peng H, James CA, Cullinan DR, Hogg GD, Mudd JL, Zuo C, Takchi R, Caldwell KE, Liu J, DeNardo DG, Fields RC, Gillanders WE, Goedegebuure SP, Hawkins WG. Neoadjuvant FOLFIRINOX Therapy Is Associated with Increased Effector T Cells and Reduced Suppressor Cells in Patients with Pancreatic Cancer. Clin Cancer Res 2021; 27:6761-6771. [PMID: 34593529 PMCID: PMC8678309 DOI: 10.1158/1078-0432.ccr-21-0998] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Revised: 06/21/2021] [Accepted: 09/24/2021] [Indexed: 01/07/2023]
Abstract
PURPOSE FOLFIRINOX has demonstrated promising results for patients with pancreatic ductal adenocarcinoma (PDAC). Chemotherapy-induced immunogenic cell death can prime antitumor immune responses. We therefore performed high-dimensional profiling of immune cell subsets in peripheral blood to evaluate the impact of FOLFIRINOX on the immune system. EXPERIMENTAL DESIGN Peripheral blood mononuclear cells (PBMC) were obtained from treatment-naïve (n = 20) and FOLFIRINOX-treated patients (n = 19) with primary PDAC tumors at the time of resection. PBMCs were characterized by 36 markers using mass cytometry by time of flight (CyTOF). RESULTS Compared with treatment-naïve patients, FOLFIRINOX-treated patients showed distinct immune profiles, including significantly decreased inflammatory monocytes and regulatory T cells (Treg), increased Th1 cells, and decreased Th2 cells. Notably, both monocytes and Treg expressed high levels of immune suppression-associated CD39, and the total CD39+ cell population was significantly lower in FOLFIRINOX-treated patients compared with untreated patients. Cellular alterations observed in responders to FOLFIRINOX included a significantly decreased frequency of Treg, an increased frequency of total CD8 T cells, and an increased frequency of CD27-Tbet+ effector/effector memory subsets of CD4 and CD8 T cells. CONCLUSIONS Our study reveals that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells. These data indicate that FOLFIRINOX neoadjuvant therapy may improve immune therapy and clinical outcome in patients with PDAC.
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Affiliation(s)
- Hui Peng
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - C Alston James
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Darren R Cullinan
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Graham D Hogg
- Department of Medicine, Washington University School of Medicine, St. Louis, Misoouri
| | - Jacqueline L Mudd
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Chong Zuo
- Department of Medicine, Washington University School of Medicine, St. Louis, Misoouri
| | - Rony Takchi
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Katharine E Caldwell
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - Jingxia Liu
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
| | - David G DeNardo
- Department of Medicine, Washington University School of Medicine, St. Louis, Misoouri
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
| | - Ryan C Fields
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
| | - William E Gillanders
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
| | - S Peter Goedegebuure
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
| | - William G Hawkins
- Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
- Siteman Cancer Center, Washington University School of Medicine, St. Louis, Missouri
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Wandmacher AM, Letsch A, Sebens S. Challenges and Future Perspectives of Immunotherapy in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13164235. [PMID: 34439389 PMCID: PMC8391691 DOI: 10.3390/cancers13164235] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/19/2021] [Accepted: 08/20/2021] [Indexed: 12/20/2022] Open
Abstract
Simple Summary Immunotherapeutic agents harness the patient’s immune system to fight cancer cells. Especially immune checkpoint inhibitors, a certain group of immunotherapeutic agents, have recently improved treatment options for many cancer types. Unfortunately, clinical trials testing of these agents in pancreatic cancer patients have not confirmed promising results from laboratory experiments. Several characteristics of pancreatic cancer biology, especially the profound tumour microenvironment that inhibits the successful identification and elimination of tumour cells by immune cells seems to be responsible for the lacking efficacy of immunotherapeutics in pancreatic cancer. We summarise recently published clinical trials investigating immunotherapeutic strategies in pancreatic cancer patients and available data on how these treatments influence pancreatic cancer biology. Moreover, we identify potential strategies to improve experimental and clinical studies in order to generate more conclusive data and improve patient outcomes in the future. Abstract To date, extensive efforts to harness immunotherapeutic strategies for the treatment of pancreatic ductal adenocarcinoma (PDAC) have yielded disappointing results in clinical trials. These strategies mainly focused on cancer vaccines and immune checkpoint inhibitors alone or in combination with chemotherapeutic or targeted agents. However, the growing preclinical and clinical data sets from these efforts have established valuable insights into the immunological characteristics of PDAC biology. Most notable are the immunosuppressive role of the tumour microenvironment (TME) and PDAC’s characteristically poor immunogenicity resulting from tumour intrinsic features. Moreover, PDAC tumour heterogeneity has been increasingly well characterized and may additionally limit a “one-fits-all” immunotherapeutic strategy. In this review, we first outline mechanisms of immunosuppression and immune evasion in PDAC. Secondly, we summarize recently published data on preclinical and clinical efforts to establish immunotherapeutic strategies for the treatment of PDAC including diverse combinatorial treatment approaches aiming at overcoming this resistance towards immunotherapeutic strategies. Particularly, these combinatorial treatment approaches seek to concomitantly increase PDAC antigenicity, boost PDAC directed T-cell responses, and impair the immunosuppressive character of the TME in order to allow immunotherapeutic agents to unleash their full potential. Eventually, the thorough understanding of the currently available data on immunotherapeutic treatment strategies of PDAC will enable researchers and clinicians to develop improved treatment regimens and to design innovative clinical trials to overcome the pronounced immunosuppression of PDAC.
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Affiliation(s)
- Anna Maxi Wandmacher
- Department of Internal Medicine II, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (A.M.W.); (A.L.)
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
| | - Anne Letsch
- Department of Internal Medicine II, University Medical Center Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; (A.M.W.); (A.L.)
| | - Susanne Sebens
- Institute for Experimental Cancer Research, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
- Correspondence:
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Nurmi AM, Mustonen H, Haglund C, Seppänen H. Changes in CRP and CA19-9 during Preoperative Oncological Therapy Predict Postoperative Survival in Pancreatic Ductal Adenocarcinoma. Oncology 2021; 99:686-698. [PMID: 34412062 DOI: 10.1159/000517835] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 06/10/2021] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Tumor and systemic inflammatory markers predict survival. This retrospective study aimed to explore the changes in CRP, CA19-9, and other routine laboratory tests during preoperative oncological therapy as prognostic factors in pancreatic ductal adenocarcinoma (PDAC). METHODS Between 2000 and 2016, 68 borderline resectable PDAC patients received preoperative oncological therapy and underwent subsequent surgery at Helsinki University Hospital, Finland. We investigated changes in CRP, CA19-9, CEA, albumin, leukocytes, bilirubin, and platelets and examined the impact on survival. RESULTS In the multivariate analysis, CRP remaining at ≥3 mg/L after preoperative oncological therapy predicted a poorer postoperative outcome when compared to CRP decreasing to or remaining at <3 mg/L (hazard ratio [HR] 2.766, 95% confidence interval [CI]: 1.300-5.885, p = 0.008). Furthermore, a CA19-9 decrease >90% during preoperative treatment predicted a favorable postoperative outcome (HR 0.297, 95% CI: 0.124-0.708, p = 0.006). In the Kaplan-Meier analysis, the median survival for patients with CRP remaining at <3 mg/L was longer than among patients with an increased CRP level at ≥3 mg/L (42 months vs. 24 months, p = 0.001). Patients with a CA19-9 decrease >90% or level normalization (to ≤37 kU/L) during preoperative treatment exhibited a median survival of 47 months; those with a 50-90% decrease, 15 months; and those with a <50% decrease, 17 months (p < 0.001). CONCLUSIONS Changes in CRP and CA19-9 during preoperative oncological therapy predict postoperative survival.
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Affiliation(s)
- Anna Maria Nurmi
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Harri Mustonen
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
| | - Caj Haglund
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Hanna Seppänen
- Department of Surgery, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.,Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Digiacomo G, Volta F, Garajova I, Balsano R, Cavazzoni A. Biological Hallmarks and New Therapeutic Approaches for the Treatment of PDAC. Life (Basel) 2021; 11:life11080843. [PMID: 34440587 PMCID: PMC8400856 DOI: 10.3390/life11080843] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/04/2021] [Accepted: 08/13/2021] [Indexed: 12/27/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is one of the deadliest solid tumors and is estimated to become a leading cause of cancer-related death in coming years. Despite advances in surgical approaches and the emergence of new chemotherapy options, its poor prognosis has not improved in the last decades. The current treatment for PDAC is the combination of cytotoxic chemotherapy agents. However, PDAC shows resistance to many antineoplastic therapies with rapid progression. Although PDAC represents a heterogeneous disease, there are common alterations including oncogenic mutations of KRAS, and the frequent inactivation of different cell cycle regulators including the CDKN2A tumor suppressor gene. An emerging field of investigation focuses on inhibiting the function of proteins that suppress the immune checkpoint PD-1/PD-L1, with activation of the endogenous immune response. To date, all conventional immunotherapies have been less successful in patients with PDAC compared to other tumors. The need for new targets, associated with an extended molecular analysis of tumor samples could give new pharmacological options for the treatment of PDAC. It is, therefore, important to push for a broader molecular approach in PDAC research. Here, we provide a selected summary of emerging strategy options for targeting PDAC using CDK4/6 inhibitors, RAS inhibitors, and new drug combinations with immune checkpoint agents.
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Affiliation(s)
- Graziana Digiacomo
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
- Correspondence: ; Tel.: +39-0521-903965
| | - Francesco Volta
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
| | - Ingrid Garajova
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy; (I.G.); (R.B.)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma, 43100 Parma, Italy; (I.G.); (R.B.)
| | - Andrea Cavazzoni
- Department of Medicine and Surgery, University of Parma, 43126 Parma, Italy; (F.V.); (A.C.)
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Xelwa N, Candy GP, Devar J, Omoshoro-Jones J, Smith M, Nweke EE. Targeting Growth Factor Signaling Pathways in Pancreatic Cancer: Towards Inhibiting Chemoresistance. Front Oncol 2021; 11:683788. [PMID: 34195085 PMCID: PMC8236623 DOI: 10.3389/fonc.2021.683788] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 05/24/2021] [Indexed: 12/15/2022] Open
Abstract
Pancreatic cancer is one of the most deadly cancers, ranking amongst the top leading cause of cancer related deaths in developed countries. Features such as dense stroma microenvironment, abnormal signaling pathways, and genetic heterogeneity of the tumors contribute to its chemoresistant characteristics. Amongst these features, growth factors have been observed to play crucial roles in cancer cell survival, progression, and chemoresistance. Here we review the role of the individual growth factors in pancreatic cancer chemoresistance. Importantly, the interplay between the tumor microenvironment and chemoresistance is explored in the context of pivotal role played by growth factors. We further describe current and future potential therapeutic targeting of these factors.
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Metabolic reprogramming due to hypoxia in pancreatic cancer: Implications for tumor formation, immunity, and more. Biomed Pharmacother 2021; 141:111798. [PMID: 34120068 DOI: 10.1016/j.biopha.2021.111798] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 05/20/2021] [Accepted: 05/29/2021] [Indexed: 01/04/2023] Open
Abstract
Hypoxia is a common phenomenon in most malignant tumors, especially in pancreatic cancer (PC). Hypoxia is the result of unlimited tumor growth and plays an active role in promoting tumor survival, progression, and invasion. As the part of the hypoxia microenvironment in PC is gradually clarified, hypoxia is becoming a key determinant and an important therapeutic target of pancreatic cancer. To adapt to the severe hypoxia environment, cells have changed their metabolic phenotypes to maintain their survival and proliferation. Enhanced glycolysis is the most prominent feature of cancer cells' metabolic reprogramming in response to hypoxia. It provides the energy source for hypoxic cancer cells (although it provides less than oxidative phosphorylation) and produces metabolites that can be absorbed and utilized by normoxic cancer cells. In addition, the uptake of glutamine and fatty acids by hypoxic cancer cells is also increased, which is also conducive to tumor progression. Their metabolites are pooled in the hexosamine biosynthesis pathway (HBP). As a nutrition sensor, HBP, in turn, can coordinate glucose and glutamine metabolism. Its end product, UDP-GlcNAc, is the substrate of protein post-translational modification (PTM) involved in various signaling pathways supporting tumor progression. Adaptive metabolic changes of cancer cells promote their survival and affect tumor immune cells in the tumor microenvironment (TME), which contributes to tumor immunosuppressive microenvironment and induces tumor immunotherapy resistance. Here, we summarize the hypoxic microenvironment, its effect on metabolic reprogramming, and its contribution to immunotherapy resistance in pancreatic cancer.
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Ding J, He X, Cheng X, Cao G, Chen B, Chen S, Xiong M. A 4-gene-based hypoxia signature is associated with tumor immune microenvironment and predicts the prognosis of pancreatic cancer patients. World J Surg Oncol 2021; 19:123. [PMID: 33865399 PMCID: PMC8053300 DOI: 10.1186/s12957-021-02204-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 03/19/2021] [Indexed: 12/17/2022] Open
Abstract
Background Pancreatic cancer (PAC) is one of the most devastating cancer types with an extremely poor prognosis, characterized by a hypoxic microenvironment and resistance to most therapeutic drugs. Hypoxia has been found to be one of the factors contributing to chemoresistance in PAC, but also a major driver of the formation of the tumor immunosuppressive microenvironment. However, the method to identify the degree of hypoxia in the tumor microenvironment (TME) is incompletely understood. Methods The mRNA expression profiles and corresponding clinicopathological information of PAC patients were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, respectively. To further explore the effect of hypoxia on the prognosis of patients with PAC as well as the tumor immune microenvironment, we established a hypoxia risk model and divided it into high- and low-risk groups in line with the hypoxia risk score. Results We established a hypoxia risk model according to four hypoxia-related genes, which could be used to demonstrate the immune microenvironment in PAC and predict prognosis. Moreover, the hypoxia risk score can act as an independent prognostic factor in PAC, and a higher hypoxia risk score was correlated with poorer prognosis in patients as well as the immunosuppressive microenvironment of the tumor. Conclusions In summary, we established and validated a hypoxia risk model that can be considered as an independent prognostic indicator and reflected the immune microenvironment of PAC, suggesting the feasibility of hypoxia-targeted therapy for PAC patients.
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Affiliation(s)
- Jianfeng Ding
- Department of General Surgery, Chaohu Hospital of Anhui Medical University, Chaohu, 238000, Anhui, China
| | - Xiaobo He
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Xiao Cheng
- Department of Pathology, School of Basic Medicine, Anhui Medical University, Hefei, 230032, Anhui, China
| | - Guodong Cao
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Bo Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China
| | - Sihan Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
| | - Maoming Xiong
- Department of General Surgery, Chaohu Hospital of Anhui Medical University, Chaohu, 238000, Anhui, China. .,Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, Anhui, China.
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Good L, Benner B, Carson WE. Bruton's tyrosine kinase: an emerging targeted therapy in myeloid cells within the tumor microenvironment. Cancer Immunol Immunother 2021; 70:2439-2451. [PMID: 33818636 PMCID: PMC8019691 DOI: 10.1007/s00262-021-02908-5] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 03/02/2021] [Indexed: 12/15/2022]
Abstract
Bruton’s tyrosine kinase (BTK) is a non-receptor kinase belonging to the Tec family of kinases. The role of BTK in B cell receptor signaling is well defined and is known to play a key role in the proliferation and survival of malignant B cells. Moreover, BTK has been found to be expressed in cells of the myeloid lineage. BTK has been shown to contribute to a variety of cellular pathways in myeloid cells including signaling in the NLRP3 inflammasome, receptor activation of nuclear factor-κβ and inflammation, chemokine receptor activation affecting migration, and phagocytosis. Myeloid cells are crucial components of the tumor microenvironment and suppressive myeloid cells contribute to cancer progression, highlighting a potential role for BTK inhibition in the treatment of malignancy. The increased interest in BTK inhibition in cancer has resulted in many preclinical studies that are testing the efficacy of using single-agent BTK inhibitors. Moreover, the ability of tumor cells to develop resistance to single-agent checkpoint inhibitors has resulted in clinical studies utilizing BTK inhibitors in combination with these agents to improve clinical responses. Furthermore, BTK regulates the immune response in microbial and viral infections through B cells and myeloid cells such as monocytes and macrophages. In this review, we describe the role that BTK plays in supporting suppressive myeloid cells, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM), while also discussing the anticancer effects of BTK inhibition and briefly describe the role of BTK signaling and BTK inhibition in microbial and viral infections.
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Affiliation(s)
- Logan Good
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - Brooke Benner
- Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA
| | - William E Carson
- Department of Surgery, Division of Surgical Oncology, Tzagournis Medical Research Facility, The Ohio State University, Columbus, OH, USA.
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LAG-3-Expressing Tumor-Infiltrating T Cells Are Associated with Reduced Disease-Free Survival in Pancreatic Cancer. Cancers (Basel) 2021; 13:cancers13061297. [PMID: 33803936 PMCID: PMC7998134 DOI: 10.3390/cancers13061297] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/09/2021] [Accepted: 03/13/2021] [Indexed: 02/08/2023] Open
Abstract
Simple Summary In light of the majority of pancreatic cancer patients not responding to current immune checkpoint blockade, alternative immunotherapeutic targets need to be identified. In this study, we employed multiplex immunofluorescence to investigate the expression of co-stimulatory and inhibitory receptors by tumor-infiltrating T cells in human pancreatic cancer. A comprehensive analysis of the receptor pattern on tumor-infiltrating T cells is essential for the development of new therapeutic strategies, as well as personalized immunotherapy, to identify patients who are likely to benefit from targeting specific immune receptors. Abstract T cells are the predominant immune cell population in the pancreatic tumor microenvironment. High CD8+ and Th1-polarized CD4+ T cell infiltration is associated with prolonged survival in human pancreatic ductal adenocarcinoma (PDAC). However, the expression pattern of co-stimulatory and inhibitory receptors by PDAC-infiltrating T cells and their prognostic significance are not well defined. In this study, we employed multiplex immunofluorescence to investigate the intratumoral expression of the co-stimulatory receptor inducible T-cell co-stimulator (ICOS), the inhibitory receptors lymphocyte-activation gene 3 (LAG-3), programmed death 1 (PD-1), and V-domain immunoglobulin suppressor of T cell activation (VISTA) by tumor-infiltrating T cells (CD3) in a cohort of 69 patients with resected PDAC. T cells were enriched particularly within the stromal area and were highly heterogeneous across tumors. Further, T cells were associated with prolonged disease-free survival (DFS). However, LAG-3 expression by PDAC-infiltrating T cells was correlated with reduced DFS. Our study highlights the biological importance of LAG-3 expression by tumor-infiltrating T cells. LAG-3+ T cells may represent a novel prognostic marker and a particularly attractive target for immunotherapeutic strategies in PDAC.
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Min AKT, Mimura K, Nakajima S, Okayama H, Saito K, Sakamoto W, Fujita S, Endo H, Saito M, Saze Z, Momma T, Ohki S, Kono K. Therapeutic potential of anti-VEGF receptor 2 therapy targeting for M2-tumor-associated macrophages in colorectal cancer. Cancer Immunol Immunother 2021; 70:289-298. [PMID: 32705303 PMCID: PMC10991089 DOI: 10.1007/s00262-020-02676-8] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Accepted: 07/17/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although immunotherapy with immune checkpoint inhibitors (ICIs) has become a standard therapeutic strategy in colorectal cancer (CRC) exhibiting microsatellite instability-high, limited patients benefit from this new approach. To increase the efficacy of ICIs in CRC patients, it is crucial to control the function of immunosuppressive cells in the tumor microenvironment. M2-tumor-associated macrophages (TAMs) are key immunosuppressive cells and promote tumor growth, angiogenesis, and epithelial-mesenchymal transition. In the present study, we focused on the VEGF signaling pathway in M2-TAMs to control their inhibitory function. METHODS We evaluated the population of M2-TAMs, the VEGF receptor 2 (VEGFR2) expression on M2-TAMs, and the correlation between HIF-1α-positive cells and VEGFR2 expression levels on M2-TAMs in CRC using the analysis of The Cancer Genome Atlas colorectal adenocarcinoma dataset (n = 592), the flow cytometry of freshly resected surgical specimens of CRC (n = 20), and the immunofluorescence staining of formalin-fixed paraffin-embedded whole tissue samples of CRC (n = 20). Furthermore, we performed a functional assay of M2 macrophages through the VEGF/VEGFR2 signaling pathway in vitro. RESULTS The population of M2-TAMs and their VEGFR2 expression significantly increased in the tumor compared to the normal mucosa in the CRC patients. HIF1-α-positive cells significantly correlated with the VEGFR2 expression level of M2-TAMs. M2 macrophages induced by cytokines in vitro produced TGF-β1 through the VEGF/VEGFR2 signaling pathway. CONCLUSIONS Our results suggest that anti-VEGFR2 therapy may have therapeutic potential to control the immune inhibitory functions of M2-TAMs in CRC, resulting in enhanced efficacy of immunotherapy with ICIs.
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Affiliation(s)
- Aung Kyi Thar Min
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Kosaku Mimura
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.
- Department of Blood Transfusion and Transplantation Immunology, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan.
| | - Shotaro Nakajima
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Hirokazu Okayama
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Katsuharu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Wataru Sakamoto
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Shotaro Fujita
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Hisahito Endo
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Motonobu Saito
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Zenichiro Saze
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Tomoyuki Momma
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Shinji Ohki
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
| | - Koji Kono
- Department of Gastrointestinal Tract Surgery, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima, Fukushima, 960-1295, Japan
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Pham TND, Shields MA, Spaulding C, Principe DR, Li B, Underwood PW, Trevino JG, Bentrem DJ, Munshi HG. Preclinical Models of Pancreatic Ductal Adenocarcinoma and Their Utility in Immunotherapy Studies. Cancers (Basel) 2021; 13:cancers13030440. [PMID: 33503832 PMCID: PMC7865443 DOI: 10.3390/cancers13030440] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/13/2021] [Accepted: 01/20/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary Immune checkpoint blockade has provided durable clinical responses in a number of human malignancies, but not in patients with pancreatic cancer. Efforts to understand mechanisms of resistance and increase efficacy of immune checkpoint blockade in pancreatic cancer require the use of appropriate preclinical models in the laboratory. Here, we discuss the benefits, caveats, and potentials for improvement of the most commonly used models, including murine-based and patient-derived models. Abstract The advent of immunotherapy has transformed the treatment landscape for several human malignancies. Antibodies against immune checkpoints, such as anti-PD-1/PD-L1 and anti-CTLA-4, demonstrate durable clinical benefits in several cancer types. However, checkpoint blockade has failed to elicit effective anti-tumor responses in pancreatic ductal adenocarcinoma (PDAC), which remains one of the most lethal malignancies with a dismal prognosis. As a result, there are significant efforts to identify novel immune-based combination regimens for PDAC, which are typically first tested in preclinical models. Here, we discuss the utility and limitations of syngeneic and genetically-engineered mouse models that are currently available for testing immunotherapy regimens. We also discuss patient-derived xenograft mouse models, human PDAC organoids, and ex vivo slice cultures of human PDAC tumors that can complement murine models for a more comprehensive approach to predict response and resistance to immunotherapy regimens.
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Affiliation(s)
- Thao N. D. Pham
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
- Correspondence: (T.N.D.P.); (H.G.M.); Tel.: +1-312-503-0312 (T.N.D.P.); +1-312-503-2301 (H.G.M.)
| | - Mario A. Shields
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
| | - Christina Spaulding
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
| | - Daniel R. Principe
- Medical Scientist Training Program, University of Illinois, Chicago, IL 60612, USA;
| | - Bo Li
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Patrick W. Underwood
- Department of Surgery, University of Florida, Gainesville, FL 32611, USA; (P.W.U.); (J.G.T.)
| | - Jose G. Trevino
- Department of Surgery, University of Florida, Gainesville, FL 32611, USA; (P.W.U.); (J.G.T.)
| | - David J. Bentrem
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
- Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA;
| | - Hidayatullah G. Munshi
- Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; (M.A.S.); (C.S.)
- Jesse Brown VA Medical Center, Chicago, IL 60612, USA;
- Robert H. Lurie Comprehensive Cancer Center, Chicago, IL 60611, USA
- Correspondence: (T.N.D.P.); (H.G.M.); Tel.: +1-312-503-0312 (T.N.D.P.); +1-312-503-2301 (H.G.M.)
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Combining CRP and CA19-9 in a novel prognostic score in pancreatic ductal adenocarcinoma. Sci Rep 2021; 11:781. [PMID: 33437015 PMCID: PMC7804300 DOI: 10.1038/s41598-020-80778-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 12/23/2020] [Indexed: 12/15/2022] Open
Abstract
Inflammation promotes tumor progression, induces invasion and metastatic spread. This retrospective study explored CRP, CA19-9, and routine laboratory values as preoperative prognostic factors in pancreatic cancer patients. Between 2000 and 2016, there were 212 surgically treated pancreatic cancer patients at Helsinki University Hospital, Finland. Out of these, 76 borderline resectable patients were treated with neoadjuvant therapy (NAT); 136 upfront resected patients were matched for age and sex at a 1:2 ratio. We analyzed preoperative CRP, CA19-9, CEA, leukocytes, albumin, bilirubin and platelets. CRP and CA19-9 were combined into a prognostic score: both CRP and CA19-9 below the cut-off values (3 mg/l and 37 kU/l, respectively), either CRP or CA19-9 above the cut-off value, and finally, both CRP and CA19-9 above the cut-off values. Among all patients, median disease-specific survival times were 54, 27 and 16 months, respectively (p < 0.001). At 5 years, among patients with CRP and CA19-9 levels below the cut-off values, 49% were alive and 45% were disease-free. Among NAT patients the corresponding survival rates were 52% and 45% and among those undergoing upfront surgery 45% and 40%, respectively. This novel prognostic score combining CRP and CA19-9 serves as a useful preoperative tool estimating survival.
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Matsuki H, Hiroshima Y, Miyake K, Murakami T, Homma Y, Matsuyama R, Morioka D, Kurotaki D, Tamura T, Endo I. Reduction of gender-associated M2-like tumor-associated macrophages in the tumor microenvironment of patients with pancreatic cancer after neoadjuvant chemoradiotherapy. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2021; 28:174-182. [PMID: 33316125 DOI: 10.1002/jhbp.883] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 11/13/2020] [Accepted: 11/20/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE This study aimed to investigate gender-dependent antitumor immune response to neoadjuvant chemoradiotherapy (NACRT) in pancreatic ductal adenocarcinoma (PDAC) patients. METHODS This study enrolled 58 patients (25 females and 33 males) with borderline resectable PDAC who underwent R0 surgical resection after NACRT. The resected tumor specimens were analyzed for tumor-associated macrophages (TAMs); tumor-infiltrating lymphocytes (CD8+ and CD4+ T cells); regulatory T cells; and IRF-5-expressing cells using immunohistochemical staining for CD163, CD204, CD8, CD4, Foxp3, and IRF-5 antigen. The relationship between clinicopathological features and clinical outcomes was evaluated using multivariate Cox proportional hazard analysis. RESULTS Females had longer overall survival (P = .044) and relapse-free survival (P = .044) than males. The CD204+ TAM number was significantly lower in females than in males (P = .009). No significant difference occurred between female and male patients in other tumor-infiltrating immune cells. IRF-5+ cell number was significantly higher in female patients (P = .002). Negative correlation occurred between CD204+ cells and IRF-5-positive cells (P = .003, r = -.385). CONCLUSIONS Female gender was an independent prognostic factor possibly due to the greater reduction in CD204+ TAM infiltration in tumors after NACRT. The beneficial effects of NACRT on TAMs' infiltration might be associated with gender-dependent IRF-5 expression.
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Affiliation(s)
- Hiroki Matsuki
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Yukihiko Hiroshima
- Department of Cancer Genomics, Kanagawa Cancer Center Research Institute, Yokohama, Japan
| | - Kentaro Miyake
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Takashi Murakami
- Department of Surgery, Teikyo University Chiba Medical Center, Ichihara, Japan
| | - Yuki Homma
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Daisuke Morioka
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Daisuke Kurotaki
- Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan
| | - Tomohiko Tamura
- Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan.,Advanced Medical Research Center, Yokohama City University, Yokohama, Japan
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Japan
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Iovanna J. Implementing biological markers as a tool to guide clinical care of patients with pancreatic cancer. Transl Oncol 2020; 14:100965. [PMID: 33248412 PMCID: PMC7704461 DOI: 10.1016/j.tranon.2020.100965] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 11/04/2020] [Accepted: 11/17/2020] [Indexed: 12/11/2022] Open
Abstract
A major obstacle for the effective treatment of PDAC is its molecular heterogeneity. Stratification of PDAC using markers highly specific, reproducible, sensitive, easily measurable and inexpensive is necessary. At the early stages, clinician’s priority lies in rapid diagnosis, so that the patient receives surgery without delay. At advanced disease stages, priority is to determine the tumor subtype and select a suitable effective treatment. A major obstacle for the effective treatment of pancreatic ductal adenocarcinoma (PDAC) is its molecular heterogeneity, reflected by the diverse clinical outcomes and responses to therapies that occur. The tumors of patients with PDAC must therefore be closely examined and classified before treatment initiation in order to predict the natural evolution of the disease and the response to therapy. To stratify patients, it is absolutely necessary to identify biological markers that are highly specific and reproducible, and easily measurable by inexpensive sensitive techniques. Several promising strategies to find biomarkers are already available or under development, such as the use of liquid biopsies to detect circulating tumor cells, circulating free DNA, methylated DNA, circulating RNA, and exosomes and extracellular vesicles, as well as immunological markers and molecular markers. Such biomarkers are capable of classifying patients with PDAC and predicting their therapeutic sensitivity. Interestingly, developing chemograms using primary cell lines or organoids and analyzing the resulting high-throughput data via artificial intelligence would be highly beneficial to patients. How can exploiting these biomarkers benefit patients with resectable, borderline resectable, locally advanced, and metastatic PDAC? In fact, the utility of these biomarkers depends on the patient's clinical situation. At the early stages of the disease, the clinician's priority lies in rapid diagnosis, so that the patient receives surgery without delay; at advanced disease stages, where therapeutic possibilities are severely limited, the priority is to determine the PDAC tumor subtype so as to estimate the clinical outcome and select a suitable effective treatment.
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Affiliation(s)
- Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, 163 Avenue de Luminy, 13288 Marseille, France.
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Immunological Gene Signature Associated With the Tumor Microenvironment of Pancreatic Cancer After Neoadjuvant Chemotherapy. Pancreas 2020; 49:1240-1245. [PMID: 32898010 DOI: 10.1097/mpa.0000000000001665] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Neoadjuvant chemotherapy (NAC) has improved overall survival in patients with pancreatic ductal adenocarcinoma (PDAC), but its effects on immune gene signatures are unknown. Here, we examined the immune transcriptome after NAC for PDAC. METHODS Resected tumor specimens were obtained from 140 patients with PDAC who received surgery first (n = 93) or NAC (n = 47). Six patients were randomly selected from each group, and RNA was extracted from tumor tissues. We compared 770 immune-related genes among the 2 groups using nCounterPanCancer Immune Profiling (NanoString Technologies, Seattle, Wash). Gene clusters were classified into 14 immune function groups based on gene ontology argolism by nSolver 4.0 software (NanoString Technologies), and corresponding immune cell function scores were compared. RESULTS Eleven genes (LY86, SH2D1A, CD247, TIGIT, CR2, CD83, LAMP3, CXCR4, DUSP4, SELL, and IL2RA) were significantly downregulated in the NAC group. Gene expression analysis showed that the functions of regulatory T cells, B cells, and natural killer CD56 dim cells were significantly decreased in the NAC group. CONCLUSIONS Neoadjuvant chemotherapy may suppress regulatory T cells and B-cell function in the PDAC microenvironment. The 11 identified genes could be useful for predicting the efficacy of NAC and could be therapeutic targets for PDAC.
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Hessmann E, Buchholz SM, Demir IE, Singh SK, Gress TM, Ellenrieder V, Neesse A. Microenvironmental Determinants of Pancreatic Cancer. Physiol Rev 2020; 100:1707-1751. [DOI: 10.1152/physrev.00042.2019] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) belongs to the most lethal solid tumors in humans. A histological hallmark feature of PDAC is the pronounced tumor microenvironment (TME) that dynamically evolves during tumor progression. The TME consists of different non-neoplastic cells such as cancer-associated fibroblasts, immune cells, endothelial cells, and neurons. Furthermore, abundant extracellular matrix components such as collagen and hyaluronic acid as well as matricellular proteins create a highly dynamic and hypovascular TME with multiple biochemical and physical interactions among the various cellular and acellular components that promote tumor progression and therapeutic resistance. In recent years, intensive research efforts have resulted in a significantly improved understanding of the biology and pathophysiology of the TME in PDAC, and novel stroma-targeted approaches are emerging that may help to improve the devastating prognosis of PDAC patients. However, none of anti-stromal therapies has been approved in patients so far, and there is still a large discrepancy between multiple successful preclinical results and subsequent failure in clinical trials. Furthermore, recent findings suggest that parts of the TME may also possess tumor-restraining properties rendering tailored therapies even more challenging.
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Affiliation(s)
- Elisabeth Hessmann
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Soeren M. Buchholz
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Ihsan Ekin Demir
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Shiv K. Singh
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Thomas M. Gress
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Volker Ellenrieder
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
| | - Albrecht Neesse
- Department of Gastroenterology, Gastrointestinal Oncology, and Endocrinology, University Medical Centre Goettingen, Georg August University, Goettingen, Germany; Department of Surgery, Klinikum rechts der Isar, Technische Universität München, School of Medicine Munich, Munich, Germany; Sonderforschungsbereich/Collaborative Research Centre 1321 Modeling and Targeting Pancreatic Cancer, Munich, Germany; Deutsches Konsortium für Translationale Krebsforschung (DKTK) Munich Site, Munich, Germany; and
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Seifert AM, Eymer A, Heiduk M, Wehner R, Tunger A, von Renesse J, Decker R, Aust DE, Welsch T, Reissfelder C, Weitz J, Schmitz M, Seifert L. PD-1 Expression by Lymph Node and Intratumoral Regulatory T Cells Is Associated with Lymph Node Metastasis in Pancreatic Cancer. Cancers (Basel) 2020; 12:cancers12102756. [PMID: 32987956 PMCID: PMC7599971 DOI: 10.3390/cancers12102756] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/17/2020] [Accepted: 09/21/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pancreatic cancer is a devastating disease and among the most immune-resistant tumor types. Single-agent immunotherapy has not demonstrated clinical benefits in pancreatic cancer patients, and combinational therapies targeting multiple mechanisms of immunosuppression are likely needed. T cell activation in lymph nodes is required for the efficacy of immunotherapy. Here, we phenotypically and functionally analyze T cells from tumor-draining lymph nodes, blood and tumors from patients with pancreatic cancer to decipher unknown immunosuppressive mechanisms and to identify potential immunotherapeutic targets. Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a mostly immunosuppressive microenvironment. Tumor-draining lymph nodes (TDLN) are a major site for priming of tumor-reactive T cells and also tumor metastasis. However, the phenotype and function of T cells in TDLNs from PDAC patients is unknown. In this study, lymph nodes from the pancreatic head (PH), the hepatoduodenal ligament (HDL) and the interaortocaval (IAC) region were obtained from 25 patients with adenocarcinoma of the pancreatic head. Additionally, tumors and matched blood were analyzed from 16 PDAC patients. Using multicolor flow cytometry, we performed a comprehensive analysis of T cells. CD4+ T cells were the predominant T cell subset in PDAC-draining lymph nodes. Overall, lymph node CD4+ and CD8+ T cells had a similar degree of activation, as measured by CD69, inducible T cell co-stimulator (ICOS) and CD137 (4-1BB) expression and interferon-γ (IFNγ) secretion. Expression of the inhibitory receptor programmed death 1 (PD-1) by lymph node and tumor-infiltrating regulatory T cells (Tregs) correlated with lymph node metastasis. Collectively, Treg cells and PD-1 are two relevant components of the immunosuppressive network in PDAC-draining lymph nodes and may be particularly attractive targets for combinatorial immunotherapeutic strategies in selected patients with node-positive PDAC.
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Affiliation(s)
- Adrian M. Seifert
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (M.H.); (J.v.R.); (R.D.); (T.W.); (J.W.); (L.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
- Correspondence:
| | - Annabel Eymer
- Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (A.E.); (R.W.); (A.T.)
| | - Max Heiduk
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (M.H.); (J.v.R.); (R.D.); (T.W.); (J.W.); (L.S.)
- National Center for Tumor Diseases (NCT), Partner Site Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Rebekka Wehner
- Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (A.E.); (R.W.); (A.T.)
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Antje Tunger
- Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (A.E.); (R.W.); (A.T.)
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Janusz von Renesse
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (M.H.); (J.v.R.); (R.D.); (T.W.); (J.W.); (L.S.)
| | - Rahel Decker
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (M.H.); (J.v.R.); (R.D.); (T.W.); (J.W.); (L.S.)
| | - Daniela E. Aust
- Department of Pathology, University Hospital Carl Gustav Carus, Medical Faculty, University of Dresden, 01307 Dresden, Germany;
- NCT Biobank Dresden, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Thilo Welsch
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (M.H.); (J.v.R.); (R.D.); (T.W.); (J.W.); (L.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
| | - Christoph Reissfelder
- Department of Surgery, Universitätsmedizin Mannheim, Medical Faculty Mannheim, Heidelberg University, 68167 Mannheim, Germany;
| | - Jürgen Weitz
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (M.H.); (J.v.R.); (R.D.); (T.W.); (J.W.); (L.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
| | - Marc Schmitz
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
- Institute of Immunology, Medical Faculty Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (A.E.); (R.W.); (A.T.)
- National Center for Tumor Diseases (NCT), University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany
| | - Lena Seifert
- Department of Visceral, Thoracic and Vascular Surgery, Medical Faculty, University Hospital Carl Gustav Carus, TU Dresden, 01307 Dresden, Germany; (M.H.); (J.v.R.); (R.D.); (T.W.); (J.W.); (L.S.)
- German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany;
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Abstract
Worldwide, approximately half a million people are diagnosed with pancreatic cancer every year, with mortality rates of more than 90%. T cells within pancreatic tumors are generally infrequent and incapable of eliciting antitumor immunity. Thus, pancreatic cancer is considered an "immunologically cold" tumor. However, recent studies clearly show that when T-cell immunity in pancreatic cancer is sufficiently induced, T cells become effective weapons. This fact suggests that to improve pancreatic cancer patients' clinical outcomes, we need to unveil the complex immune biology of this disease. In this review, we discuss the elements of tumor immunogenicity in the specific context of pancreatic malignancy.
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Shah VM, Sheppard BC, Sears RC, Alani AW. Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer. Cancer Lett 2020; 492:63-70. [PMID: 32822815 DOI: 10.1016/j.canlet.2020.07.041] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/24/2020] [Accepted: 07/30/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors with an overall five-year survival rate of that has only just reached 10%. The tumor microenvironment of PDAC is characterized by desmoplasia, which consist of dense stroma of fibroblasts and inflammatory cells, resulting in a hypoxic environment due to limited oxygen diffusion through the tumor. Hypoxia contributes to the aggressive tumor biology by promoting tumor progression, malignancy, and promoting resistance to conventional and targeted therapeutic agents. In depth research in the area has identified that hypoxia modulates the tumor biology through hypoxia inducible factors (HIFs), which not only are the key determinant of pancreatic malignancy but also an important target for therapy. In this review, we summarize the recent advances in understanding hypoxia driven phenotypes, which are responsible for the highly aggressive and metastatic characteristics of pancreatic cancer, and how hypoxia can be exploited as a target for drug delivery.
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Affiliation(s)
- Vidhi M Shah
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University/OHSU, 2730 SW Moody Ave., Portland, OR, 97201, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S. W. Sam Jackson Park Rd., Portland, OR, 97239, USA
| | - Brett C Sheppard
- Department of Surgery, Oregon Health and Science University, 3181 S.W. Sam Jackson Park Road, Portland, OR, 97239, USA; Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA
| | - Rosalie C Sears
- Brenden-Colson Center for Pancreatic Care, Oregon Health and Science University, 3181 S.W Sam Jackson Park Road, Portland, OR, 97239, USA; Department of Molecular and Medical Genetics, Oregon Health and Science University, 3181 S. W. Sam Jackson Park Rd., Portland, OR, 97239, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA
| | - Adam Wg Alani
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University/OHSU, 2730 SW Moody Ave., Portland, OR, 97201, USA; OHSU Knight Cancer Institute at Oregon Health & Science University, Portland, OR, 97239, USA; Department of Biomedical Engineering, School of Medicine at Oregon Health & Science University, Portland, OR, 97239, USA.
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Pointer DT, Roife D, Powers BD, Murimwa G, Elessawy S, Thompson ZJ, Schell MJ, Hodul PJ, Pimiento JM, Fleming JB, Malafa MP. Neutrophil to lymphocyte ratio, not platelet to lymphocyte or lymphocyte to monocyte ratio, is predictive of patient survival after resection of early-stage pancreatic ductal adenocarcinoma. BMC Cancer 2020; 20:750. [PMID: 32782024 PMCID: PMC7422564 DOI: 10.1186/s12885-020-07182-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/14/2020] [Indexed: 12/11/2022] Open
Abstract
Background NLR, PLR, and LMR have been associated with pancreatic ductal adenocarcinoma (PDAC) survival. Prognostic value and optimal cutpoints were evaluated to identify underlying significance in surgical PDAC patients. Methods NLR, PLR, and LMR preoperative values were available for 277 PDAC patients who underwent resection between 2007 and 2015. OS, RFS, and survival probability estimates were calculated by univariate, multivariable, and Kaplan-Meier analyses. Continuous and dichotomized ratio analysis determined best-fit cutpoints and assessed ratio components to determine primary drivers. Results Elevated NLR and PLR and decreased LMR represented 14%, 50%, and 50% of the cohort, respectively. OS (P = .002) and RFS (P = .003) were significantly decreased in resected PDAC patients with NLR ≥5 compared to those with NLR < 5. Optimal prognostic OS and RFS cutpoints for NLR, PLR, and LMR were 4.8, 192.6, and 1.7, respectively. Lymphocytes alone were the primary prognostic driver of NLR, demonstrating identical survival to NLR. Conclusions NLR is a significant predictor of OS and RFS, with lymphocytes alone as its primary driver; we identified optimal cutpoints that may direct future investigation of their prognostic value. This study contributes to the growing evidence of immune system influence on outcomes in early-stage pancreatic cancer.
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Affiliation(s)
- David T Pointer
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA
| | - David Roife
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA
| | - Benjamin D Powers
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA
| | - Gilbert Murimwa
- Department of Surgery, University of Texas Southwestern, Dallas, TX, USA
| | - Sameh Elessawy
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA
| | - Zachary J Thompson
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Michael J Schell
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Pamela J Hodul
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA
| | - Jose M Pimiento
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA
| | - Mokenge P Malafa
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center and Research Institute, 12902 USF Magnolia Dr, Tampa, FL, 33612, USA.
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Papalampros A, Vailas M, Ntostoglou K, Chiloeches ML, Sakellariou S, Chouliari NV, Samaras MG, Veltsista PD, Theodorou SDP, Margetis AT, Bergonzini A, Karydakis L, Hasemaki N, Havaki S, Moustakas II, Chatzigeorgiou A, Karamitros T, Patsea E, Kittas C, Lazaris AC, Felekouras E, Gorgoulis VG, Frisan T, Pateras IS. Unique Spatial Immune Profiling in Pancreatic Ductal Adenocarcinoma with Enrichment of Exhausted and Senescent T Cells and Diffused CD47-SIRPα Expression. Cancers (Basel) 2020; 12:1825. [PMID: 32645996 PMCID: PMC7408661 DOI: 10.3390/cancers12071825] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/01/2020] [Accepted: 07/02/2020] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is resistant to single-agent immunotherapies. To understand the mechanisms leading to the poor response to this treatment, a better understanding of the PDAC immune landscape is required. The present work aims to study the immune profile in PDAC in relationship to spatial heterogeneity of the tissue microenvironment (TME) in intact tissues. METHODS Serial section and multiplex in situ analysis were performed in 42 PDAC samples to assess gene and protein expression at single-cell resolution in the: (a) tumor center (TC), (b) invasive front (IF), (c) normal parenchyma adjacent to the tumor, and (d) tumor positive and negative draining lymph nodes (LNs). RESULTS We observed: (a) enrichment of T cell subpopulations with exhausted and senescent phenotype in the TC, IF and tumor positive LNs; (b) a dominant type 2 immune response in the TME, which is more pronounced in the TC; (c) an emerging role of CD47-SIRPα axis; and (d) a similar immune cell topography independently of the neoadjuvant chemotherapy. CONCLUSION This study reveals the existence of dysfunctional T lymphocytes with specific spatial distribution, thus opening a new dimension both conceptually and mechanistically in tumor-stroma interaction in PDAC with potential impact on the efficacy of immune-regulatory therapeutic modalities.
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Affiliation(s)
- Alexandros Papalampros
- First Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.P.); (M.V.); (L.K.); (N.H.); (E.F.)
| | - Michail Vailas
- First Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.P.); (M.V.); (L.K.); (N.H.); (E.F.)
| | - Konstantinos Ntostoglou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
| | - Maria Lopez Chiloeches
- Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden; (M.L.C.); (A.B.); (T.F.)
| | - Stratigoula Sakellariou
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.S.); (A.C.L.)
| | - Niki V. Chouliari
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
| | - Menelaos G. Samaras
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
| | - Paraskevi D. Veltsista
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
- Oncology, School of Medical Sciences, Vrije Universiteit Amsterdam, De Boelelaan, 1117 Amsterdam, The Netherlands
| | - Sofia D. P. Theodorou
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
| | - Aggelos T. Margetis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
| | - Anna Bergonzini
- Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden; (M.L.C.); (A.B.); (T.F.)
| | - Lysandros Karydakis
- First Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.P.); (M.V.); (L.K.); (N.H.); (E.F.)
| | - Natasha Hasemaki
- First Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.P.); (M.V.); (L.K.); (N.H.); (E.F.)
| | - Sophia Havaki
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
| | - Ioannis I. Moustakas
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.C.)
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (I.I.M.); (A.C.)
- Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Department of Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Eleni Patsea
- Department of Pathology, Metropolitan General Hospital of Athens, 15562 Cholargos, Greece;
| | - Christos Kittas
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
| | - Andreas C. Lazaris
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.S.); (A.C.L.)
| | - Evangelos Felekouras
- First Department of Surgery, Laikon University Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece; (A.P.); (M.V.); (L.K.); (N.H.); (E.F.)
| | - Vassilis G. Gorgoulis
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
- Faculty of Biology, Medicine and Health Manchester Cancer Research Centre, Manchester Academic Health Sciences Centre, The University of Manchester, Manchester M20-4GJ, UK
- Center for New Biotechnologies and Precision Medicine, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Str, 11527 Athens, Greece
- Basic Research, Biomedical Research Foundation of the Academy of Athens, 11527 Athens, Greece
| | - Teresa Frisan
- Department of Molecular Biology, Umeå University, 90187 Umeå, Sweden; (M.L.C.); (A.B.); (T.F.)
- Department of Cell and Molecular Biology, Karolinska Institutet, 17177 Stockholm, Sweden
| | - Ioannis S. Pateras
- Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece; (K.N.); (N.V.C.); (M.G.S.); (P.D.V.); (S.D.P.T.); (A.T.M.); (S.H.); (C.K.); (V.G.G.)
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Colloca GA, Venturino A, Guarneri D. Neutrophil count kinetics during the first cycle of chemotherapy predicts the outcome of patients with locally advanced or metastatic pancreatic cancer. Asia Pac J Clin Oncol 2020; 16:247-253. [PMID: 32129930 DOI: 10.1111/ajco.13325] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 01/28/2020] [Indexed: 01/04/2023]
Abstract
BACKGROUND Neutrophil count reduction after chemotherapy has been related with longer survival of patients with metastatic pancreatic adenocarcinoma, but there is not a standardized measurement for this phenomenon. METHODS Some parameters related to the change in neutrophil count between the first and the second cycle of chemotherapy or between the baseline count and the nadir have been evaluated among patients with advanced pancreatic cancer at a single institution. A Cox regression model was built which included, in addition to the common prognostic variables, some variables related to the change of the neutrophil count after chemotherapy. RESULTS One hundred patients were selected. Two neutrophil kinetics related variables predicted overall survival independently, such as the neutrophil count growth rate (hazard ratio [HR] = 1.245; confidence intervals [CIs], 1.077-1.440) and the chemotherapy-induced neutropenia after one cycle (HR = 0.499; CIs, 0.269-0.927). CONCLUSION The kinetics of neutrophil count after chemotherapy is an early and independent prognostic factor, which appears to be simple to measure at the start of the second cycle of chemotherapy by means of the neutrophil count growth rate.
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Fan JQ, Wang MF, Chen HL, Shang D, Das JK, Song J. Current advances and outlooks in immunotherapy for pancreatic ductal adenocarcinoma. Mol Cancer 2020; 19:32. [PMID: 32061257 PMCID: PMC7023714 DOI: 10.1186/s12943-020-01151-3] [Citation(s) in RCA: 141] [Impact Index Per Article: 28.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 02/06/2020] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an incurable cancer resistant to traditional treatments, although a limited number of early-stage patients can undergo radical resection. Immunotherapies for the treatment of haematological malignancies as well as solid tumours have been substantially improved over the past decades, and impressive results have been obtained in recent preclinical and clinical trials. However, PDAC is likely the exception because of its unique tumour microenvironment (TME). In this review, we summarize the characteristics of the PDAC TME and focus on the network of various tumour-infiltrating immune cells, outlining the current advances in PDAC immunotherapy and addressing the effect of the PDAC TME on immunotherapy. This review further explores the combinations of different therapies used to enhance antitumour efficacy or reverse immunodeficiencies and describes optimizable immunotherapeutic strategies for PDAC. The concordant combination of various treatments, such as targeting cancer cells and the stroma, reversing suppressive immune reactions and enhancing antitumour reactivity, may be the most promising approach for the treatment of PDAC. Traditional treatments, especially chemotherapy, may also be optimized for individual patients to remodel the immunosuppressive microenvironment for enhanced therapy.
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Affiliation(s)
- Jia-qiao Fan
- Third General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Meng-Fei Wang
- Third General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Hai-Long Chen
- Third General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Dong Shang
- Third General Surgery Department, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Jugal K. Das
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, TX USA
| | - Jianxun Song
- Department of Microbial Pathogenesis and Immunology, Texas A&M University Health Science Center, College Station, TX USA
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