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Johnson BA, Parimi V, Kamanda S, Corney DC, Choi W, Hoffman‐Censits J, Kates M, McConkey DJ, Hahn NM, Matoso A. Sarcomatoid areas of urothelial carcinoma are enriched for CD163-positive antigen-presenting cells. J Pathol Clin Res 2025; 11:e70021. [PMID: 39971624 PMCID: PMC11839278 DOI: 10.1002/2056-4538.70021] [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: 10/25/2024] [Revised: 01/24/2025] [Accepted: 01/29/2025] [Indexed: 02/21/2025]
Abstract
Sarcomatoid urothelial carcinoma (SUC) is a rare histologic subtype with poor prognosis. While there is known intra-tumoral heterogeneity between individual SUC tumors, the relationship between sarcomatoid and conventional urothelial carcinoma (CUC) within the same patient is poorly understood. The objective of this study was to identify differences between the sarcomatoid and CUC tumor microenvironment components that may drive this aggressive phenotype. Using tissue microarrays from eight patient tumors with mixed CUC and SUC, we examined paired CUC, mixed urothelial carcinoma (UC) regions, and SUC using the Nanostring Digital Spatial Profiling platform. We found SUC and mixed UC had higher levels of stromal cells, predominately macrophages and fibroblasts, when compared with CUC within the same tumor. CD14, CD163, and transforming growth factor-beta levels were significantly higher in SUC than in CUC. Immunohistochemical analysis revealed consistently moderate to strong expression of CD163-positive antigen-presenting cells (APCs) in SUC regions, whereas CD68-positive APC expression was generally absent. Thus, in mixed histology SUC, the SUC component preferentially expressed CD163-positive APCs and fibroblasts compared to the CUC component. As CD163-positive APCs and fibroblasts are known to be tumor-promoting and immune-suppressive, this infiltration may contribute to epithelial to mesenchymal transition and other aggressive properties of SUC.
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MESH Headings
- Humans
- CD163 Antigen
- Antigens, Differentiation, Myelomonocytic/metabolism
- Antigens, Differentiation, Myelomonocytic/analysis
- Antigens, CD/metabolism
- Antigens, CD/analysis
- Receptors, Cell Surface/metabolism
- Receptors, Cell Surface/analysis
- Tumor Microenvironment/immunology
- Urinary Bladder Neoplasms/pathology
- Urinary Bladder Neoplasms/immunology
- Antigen-Presenting Cells/immunology
- Antigen-Presenting Cells/pathology
- Carcinoma, Transitional Cell/pathology
- Carcinoma, Transitional Cell/immunology
- Biomarkers, Tumor/analysis
- Male
- Female
- Urothelium/pathology
- Urothelium/immunology
- Aged
- Middle Aged
- Macrophages
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Affiliation(s)
- Burles A Johnson
- Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
- Department of UrologyJohns Hopkins Greenberg Bladder Cancer InstituteBaltimoreMarylandUSA
| | - Vamsi Parimi
- Department of PathologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
| | - Sonia Kamanda
- Department of PathologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
| | - David C Corney
- MultiomicsAzenta Life SciencesSouth PlainfieldNew JerseyUSA
| | - Woonyoung Choi
- Department of UrologyJohns Hopkins Greenberg Bladder Cancer InstituteBaltimoreMarylandUSA
- Department of UrologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
| | - Jean Hoffman‐Censits
- Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
- Department of UrologyJohns Hopkins Greenberg Bladder Cancer InstituteBaltimoreMarylandUSA
- Department of UrologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
| | - Max Kates
- Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
- Department of UrologyJohns Hopkins Greenberg Bladder Cancer InstituteBaltimoreMarylandUSA
- Department of UrologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
| | - David J McConkey
- Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
- Department of UrologyJohns Hopkins Greenberg Bladder Cancer InstituteBaltimoreMarylandUSA
- Department of UrologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
| | - Noah M Hahn
- Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
- Department of UrologyJohns Hopkins Greenberg Bladder Cancer InstituteBaltimoreMarylandUSA
- Department of UrologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
| | - Andres Matoso
- Department of OncologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
- Department of UrologyJohns Hopkins Greenberg Bladder Cancer InstituteBaltimoreMarylandUSA
- Department of PathologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
- Department of UrologyThe Johns Hopkins Medical InstitutionsBaltimoreMarylandUSA
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Huang CX, Siwan E, Baker CJ, Wei Z, Shinko D, McGuire HM, Twigg SM, Min D. Uncovering Sex-Related Differences in Skin Macrophage Polarization During Wound Healing in Diabetic Mice. FRONT BIOSCI-LANDMRK 2025; 30:27113. [PMID: 40018936 DOI: 10.31083/fbl27113] [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: 10/24/2024] [Revised: 12/12/2024] [Accepted: 12/20/2024] [Indexed: 03/01/2025]
Abstract
BACKGROUND Chronic wounds, such as diabetes-related foot ulcers, arise from delayed wound healing and create significant health and economic burdens. Macrophages regulate healing by shifting between pro- and anti-inflammatory phenotypes, known as macrophage polarization. Sex and diabetes can impair wound healing, but their influence on macrophage phenotype in skin tissue during wound healing remains unclear, which was investigated in this study using a novel two-sex diabetic mouse model. METHODS Diabetes was induced in male and female C57BL/6J mice using low-dose streptozotocin injections and high-fat diet feeding, with chow-fed mice as controls. After 18 weeks, each mouse received four circular full-thickness dorsal skin wounds. The macrophage phenotypes in wounded skin tissues at Day 0 and Day 10 post-wounding were analyzed using mass cytometry with manual gating and automated computational clustering. RESULTS Male diabetic mice exhibited more severe hyperglycemia and insulin resistance compared to females. Although diabetic mice did not display delayed wound healing, male mice had a greater proportion of total macrophages than females, especially a higher proportion of pro-inflammatory matrix metalloproteinase-9 (MMP-9)+ macrophages and a lower proportion of anti-inflammatory adiponectin receptor 1 (AdipoR1)+ macrophages in male diabetic mice compared to females, indicating an imbalanced polarization towards a pro-inflammatory phenotype that could result in poorer wound healing. Interestingly, computational clustering identified a new pro-inflammatory, pro-healing phenotype (Ly6C+AdipoR1+CD163-CD206-) more abundant in females than males, suggesting this phenotype may play a role in the transition from the inflammatory to the proliferative stage of wound healing. CONCLUSIONS This study demonstrated a significant sex-based difference in macrophage populations, with male diabetic mice showing a pro-inflammatory bias that may impair wound healing, while a unique pro-inflammatory, pro-healing macrophage population more abundant in females could facilitate recovery. Further research is needed to investigate the role of these newly identified phenotypes in regulating impaired wound healing.
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Affiliation(s)
- Coco X Huang
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
| | - Elisha Siwan
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
| | - Callum J Baker
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
- School of Health Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW 2006, Australia
| | - Zhuoran Wei
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
| | - Diana Shinko
- Sydney Cytometry, The University of Sydney, Sydney, NSW 2006, Australia
| | - Helen M McGuire
- School of Medical Sciences, Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
| | - Stephen M Twigg
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
| | - Danqing Min
- Greg Brown Diabetes and Endocrine Research Laboratory, Sydney Medical School (Central), Faculty of Medicine and Health, Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia
- Department of Endocrinology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia
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Liu SY, Hsu CL, Yang SF, Lee HS, Sheu JC, Weng MT. Intratumoral administration of poly-ICLC enhances the antitumor effects of anti-PD-1. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2025; 32:139-150. [PMID: 39538381 DOI: 10.1002/jhbp.12088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
BACKGROUND Immune checkpoint inhibitors are effective to treat hepatocellular carcinoma (HCC) yet only successful in a small part of patients. This study aimed to investigate whether poly-ICLC, an immune stimulant, can enhance the antitumor effects of anti-PD-1 on mouse HCC. METHODS We established two syngeneic HCC mouse models with BNL cells in BALB/c mice and Hep-55.1 C cells in C57BL/6 J mice. Mice with subcutaneous HCC tumors received one of five treatments: control, anti-PD-1, intratumoral (IT) poly-ICLC, anti-PD-1 plus intramuscular (IM) poly-ICLC, or anti-PD-1 plus IT poly-ICLC. Tumor volumes were measured, CD8+ T lymphocytes in tumors and spleen were analyzed, and interferon-γ activity was assessed by ELISpot. Immune cell types and abundance were evaluated with NanoString nCounter IO360 panels. RESULTS Cotreatment with poly-ICLC significantly enhanced the antitumor effects of anti-PD-1, with IT administration being more effective than IM. IT poly-ICLC also induced more significant CD8+ T cell infiltration and interferon-γ activity in the tumor and spleen, and more upregulation of both interferon-γ and M1 macrophage signals in the tumor microenvironment while downregulating several cancer-promoting pathways. CONCLUSIONS Combination therapy with poly-ICLC, especially through IT route, and anti-PD-1 provides significantly greater antitumor effects than anti-PD-1 monotherapy in syngeneic mouse models of HCC.
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Affiliation(s)
- Shin-Yun Liu
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Shih-Feng Yang
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
| | - Hsuan-Shu Lee
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Jin-Chuan Sheu
- Liver Disease Prevention and Treatment Research Foundation, Taipei, Taiwan
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
| | - Meng-Tzu Weng
- Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Department of Medical Research, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, Taiwan
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Zhou Z, Ge S, Gu C, Chen J, Lu C, Liu Y, Jiang S. Improving Outcomes in Hepatocellular Carcinoma through Integration of Machine Learning: Development of a Tumor-Associated Macrophage Signature. Dig Dis 2025; 43:190-205. [PMID: 39894017 DOI: 10.1159/000543642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 01/14/2025] [Indexed: 02/04/2025]
Abstract
INTRODUCTION Hepatocellular carcinoma (HCC) is one of the most common malignant tumors globally. Macrophages, as essential components of the immune system, play crucial roles in immune regulation, inflammation modulation, and antitumor activity. However, it remains unclear whether tumor-associated macrophages can serve as prognostic markers for HCC. METHODS First, we identified tumor-associated macrophages based on single-cell data from GSE140228. Then, using a machine learning approach with a combination of 101 module genes, we constructed an optimal prognostic model. Subsequently, we compared our constructed model with other published prognostic models for HCC. Finally, we utilized the generated model score to predict the response to chemotherapy and immune therapy. RESULTS First, we identified clusters of tumor-associated macrophages using single-cell data. Subsequently, we calculated the tumor-associated macrophage score based on module genes from the previous step. Compared to traditional clinical indicators, tumor-associated macrophage signature (TAMS) exhibits significant advantages. The TAMS C-index not only predicts overall survival, but also recurrence-free survival in HCC patients. Additionally, there was a higher prevalence of TP53 mutations in HCC patients with high TAMS. Furthermore, patients with low TAMS showed greater sensitivity to immunotherapy compared to those with high TAMS. Notably, the number and intensity of interactions between TAM and other T lymphocytes were significantly higher than those involving other cell populations. Interestingly, the high TAMS group exhibited significantly elevated levels of immune checkpoint markers and M2 macrophage markers. CONCLUSION TAMS can serve as a novel and potent tool, offering improved treatment options and prognostic assessment for patients with HCC.
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Affiliation(s)
- Zicheng Zhou
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China,
| | - Sijia Ge
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Chiyu Gu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Jing Chen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Yanhua Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, China
| | - Sutian Jiang
- Department of Pathology, Lishui People's Hospital, Lishui, China
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Bannister ME, Chatterjee DA, Shetty S, Patten DA. The Role of Macrophages in Hepatocellular Carcinoma and Their Therapeutic Potential. Int J Mol Sci 2024; 25:13167. [PMID: 39684877 DOI: 10.3390/ijms252313167] [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: 10/14/2024] [Revised: 12/05/2024] [Accepted: 12/06/2024] [Indexed: 12/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC) represents a significant clinical burden globally and is predicted to continue to increase in incidence for the foreseeable future. The treatment of HCC is complicated by the fact that, in the majority of cases, it develops on a background of advanced chronic inflammatory liver disease. Chronic inflammation can foster an immunosuppressive microenvironment that promotes tumour progression and metastasis. In this setting, macrophages make up a major immune component of the HCC tumour microenvironment, and in this review, we focus on their contribution to HCC development and progression. Tumour-associated macrophages (TAMs) are largely derived from infiltrating monocytes and their potent anti-inflammatory phenotype can be induced by factors that are found within the tumour microenvironment, such as growth factors, cytokines, hypoxia, and extracellular matrix (ECM) proteins. In general, experimental evidence suggest that TAMs can exhibit a variety of functions that aid HCC tumour progression, including the promotion of angiogenesis, resistance to drug therapy, and releasing factors that support tumour cell proliferation and metastasis. Despite their tumour-promoting profile, there is evidence that the underlying plasticity of these cells can be targeted to help reprogramme TAMs to drive tumour-specific immune responses. We discuss the potential for targeting TAMs therapeutically either by altering their phenotype within the HCC microenvironment or by cell therapy approaches by taking advantage of their infiltrative properties from the circulation into tumour tissue.
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Affiliation(s)
- Megan E Bannister
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
| | - Devnandan A Chatterjee
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
- National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - Shishir Shetty
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
- National Institute for Health Research, Birmingham Biomedical Research Centre at University Hospitals Birmingham NHS Foundation Trust, Birmingham B15 2TH, UK
| | - Daniel A Patten
- Centre for Liver and Gastrointestinal Research, School of Infection, Inflammation and Immunology, University of Birmingham, Birmingham B15 2TT, UK
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Wu X, Fang S. Comparison of differences in immune cells and immune microenvironment among different kinds of oncolytic virus treatments. Front Immunol 2024; 15:1494887. [PMID: 39588373 PMCID: PMC11586384 DOI: 10.3389/fimmu.2024.1494887] [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: 09/11/2024] [Accepted: 10/24/2024] [Indexed: 11/27/2024] Open
Abstract
Oncolytic viruses are either naturally occurring or genetically engineered viruses that can activate immune cells and selectively replicate in and destroy cancer cells without damaging healthy tissues. Oncolytic virus therapy (OVT) represents an emerging treatment approach for cancer. In this review, we outline the properties of oncolytic viruses and then offer an overview of the immune cells and tumor microenvironment (TME) across various OVTs. A thorough understanding of the immunological mechanisms involved in OVTs could lead to the identification of novel and more effective therapeutic targets for cancer treatment.
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Affiliation(s)
| | - Shaokuan Fang
- Department of Neurology, Neuroscience Centre, The First Hospital of Jilin University, Changchun, China
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Fernando V, Zheng X, Sharma V, Sweef O, Choi ES, Furuta S. Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism. Life Sci Alliance 2024; 7:e202302339. [PMID: 39191486 PMCID: PMC11350068 DOI: 10.26508/lsa.202302339] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 08/16/2024] [Accepted: 08/19/2024] [Indexed: 08/29/2024] Open
Abstract
HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor-associated macrophages (TAMs). Although TAMs consist of the immune-stimulatory M1 type and immune-suppressive M2 type, the M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1- versus M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- versus M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-like macrophages, which then redirects arginine metabolism to NO synthesis and converts M2 type to M1 type. The reprogrammed macrophages exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in the metabolic shift of the HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.
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Affiliation(s)
- Veani Fernando
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH, USA
- Division of Rheumatology, University of Colorado, Anschutz Medical Campus Barbara Davis Center, Aurora, CO, USA
| | - Xunzhen Zheng
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH, USA
| | - Vandana Sharma
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH, USA
- Department of Zoology and Physiology, University of Wyoming, Laramie, WY, USA
| | - Osama Sweef
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Eun-Seok Choi
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA
| | - Saori Furuta
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, Toledo, OH, USA
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, Cleveland, OH, USA
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Theodoraki MN, Huber D, Hofmann L, Werner L, Idel C, Fleckner J, Plötze-Martin K, Schütt L, Brunner C, Depping R, Hoffmann TK, Bruchhage KL, Pries R. Type 2-like polarization and elevated CXCL4 secretion of monocyte derived macrophages upon internalization of plasma-derived exosomes from head and neck cancer patients. BMC Cancer 2024; 24:1173. [PMID: 39304856 PMCID: PMC11414076 DOI: 10.1186/s12885-024-12948-6] [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: 06/20/2024] [Accepted: 09/12/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Exosomes are closely associated with different aspects of tumor-progression in patients with head and neck squamous cell carcinoma (HNSCC), such as angiogenesis or immune regulation. As extracellular vesicles they are involved in the intercellular communication by transferring their cargo such as proteins and nucleic acids from one cell to another. However, the influence of tumor related plasma-derived exosomes on the polarization and characteristics of monocyte derived macrophages is not fully understood. METHODS Exosomes were isolated from plasma samples of healthy donors (HD) and HNSCC patients and further evaluated with regard to morphology, size and protein composition via transmission electron microscopy, nanoparticle tracking, western blot analysis and cytokine assays. Differentiation and characteristics of monocyte derived macrophages upon exosome internalization were analyzed using flow cytometry and fluorescence microscopy. Macrophage cytokine secretion patterns were analyzed by human cytokine antibody arrays and ELISA measurements. RESULTS Our data revealed elevated overall plasma levels of CTLA-4, PD-L1, and TIM-3 as well as elevated exosome-associated CTLA-4, PD-L2, TIM-3, and LAG-3 levels in HNSCC patients compared to HD. Furthermore, we observed a significant type 2-like polarization and elevated CXCL4 secretion of monocyte derived macrophages upon internalization of plasma-derived exosomes from HNSCC patients, which could be visualized by fluorescence microcopy of membrane stained exosomes. CONCLUSIONS The study provides new insights regarding exosome driven pro-tumorigenic immune regulation in the circulation of patients with head and neck cancer and could help to better understand the individual immunologic situation.
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Affiliation(s)
- Marie-Nicole Theodoraki
- Department of Otorhinolaryngology, Ulm University Medical Center, Ulm, Germany
- Department of Otolaryngology, Head and Neck Surgery, School of Medicine and Health, Technical University of Munich (TUM), Munich, Germany
| | - Diana Huber
- Department of Otorhinolaryngology, Ulm University Medical Center, Ulm, Germany
| | - Linda Hofmann
- Department of Otorhinolaryngology, Ulm University Medical Center, Ulm, Germany
| | - Lotte Werner
- Department of Otorhinolaryngology, University of Luebeck, Luebeck, Germany
| | - Christian Idel
- Department of Otorhinolaryngology, University of Luebeck, Luebeck, Germany
| | - Jonas Fleckner
- Department of Otorhinolaryngology, University of Luebeck, Luebeck, Germany
| | | | - Lutz Schütt
- Department of Otorhinolaryngology, Ulm University Medical Center, Ulm, Germany
| | - Cornelia Brunner
- Department of Otorhinolaryngology, Ulm University Medical Center, Ulm, Germany
| | - Reinhard Depping
- Institute of Physiology, Working Group Hypoxia, University of Luebeck, Luebeck, Germany
| | - Thomas K Hoffmann
- Department of Otorhinolaryngology, Ulm University Medical Center, Ulm, Germany
| | | | - Ralph Pries
- Department of Otorhinolaryngology, University of Luebeck, Luebeck, Germany.
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Jeibouei S, Monfared AK, Hojat A, Aref AR, Shams F, Dolati M, Moradi A, Hosseini M, Javadi SM, Ajoudanian M, Molavi Z, Moghaddam M, Mohammadi F, Nuoroozi G, Naeimi SK, Shahani M, Zali H, Akbari ME, Mostafavi E. Human-derived Tumor-On-Chip model to study the heterogeneity of breast cancer tissue. BIOMATERIALS ADVANCES 2024; 162:213915. [PMID: 38878646 DOI: 10.1016/j.bioadv.2024.213915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 05/19/2024] [Accepted: 05/29/2024] [Indexed: 07/03/2024]
Abstract
One of the leading causes that complicate the treatment of some malignancies, including breast cancer, is tumor heterogeneity. In addition to inter-heterogeneity and intra-heterogeneity of tumors that reflect the differences between cancer cell characteristics, heterogeneity in the tumor microenvironment plays a critical role in tumor progression and could be considered an overlooked and a proper target for the effective selection of therapeutic approaches. Due to the difficulty of completely capturing tumor heterogeneity in conventional detection methods, Tumor-on-Chip (TOC) devices with culturing patient-derived spheroids could be an appropriate alternative. In this research, human-derived spheroids from breast cancer individuals were cultured for 6 days in microfluidic devices. To compare TOC data with conventional detection methods, immunohistochemistry (IHC) and ITRAQ data were employed, and various protein expressions were validated using the transcriptomic databases. The behavior of the spheroids in the collagen matrix and the cell viability were monitored over 6 days of culture. IHC and immunocytochemistry (ICC) results revealed that inter and intra-heterogeneity of tumor spheroids are associated with HER2/ER expression. HER2 expression levels revealed a more important biomarker associated with invasion in the 3D culturing of spheroids. The expression levels of CD163 (as a marker for Ma2 macrophages) and CD44 (a marker for cancer stem cells (CSCs)) were also evaluated. Interestingly, the levels of M2a macrophages and CSCs were higher in triple-negative specimens and samples that showed higher migration and invasion. Cell density and extracellular matrix (ECM) stiffness were also important factors affecting the migration and invasion of the spheroids through the matrix. Among these, rigid ECM revealed a more crucial role than cell density. To sum up, these research findings demonstrated that human-derived spheroids from breast cancer specimens in microfluidic devices provide a dynamic condition for predicting tumor heterogeneity in patients, which can help move the field forward for better and more accurate therapeutic strategies.
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Affiliation(s)
- Shabnam Jeibouei
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran; Virginia Seafood Agricultural Research and Extension Center, Virginia Tech, Hampton, VA 23669, USA
| | - Arefeh Khazraie Monfared
- William Harvey Research Institute, Faculty of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
| | - Ali Hojat
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Amir Reza Aref
- Department of surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Vitro Vision, DeepkinetiX Inc, Boston, MA, USA
| | - Forough Shams
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mandana Dolati
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Afshin Moradi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Masoumeh Hosseini
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Seyed Mohammadreza Javadi
- Department of Surgery, School of Medicine, Besat Hospital, Hamadan University of Medical Sciences, Hamadan 65178-38636, Iran
| | - Mohammad Ajoudanian
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zahra Molavi
- Proteomics Research Center, Shahid Beheshti University of Medical Science, Tehran 19839-63113, Iran
| | - Maryam Moghaddam
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Farzaneh Mohammadi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Ghader Nuoroozi
- Men's Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sahar Khakpour Naeimi
- Islamic Azad University, Central Tehran Branch, Faculty of Basic Sciences, Department of Biology, Tehran 63537-11489, Iran
| | - Minoo Shahani
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran
| | - Hakimeh Zali
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran; Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran.
| | - Mohammad Esmaeil Akbari
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran 19839-63113, Iran.
| | - Ebrahim Mostafavi
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
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10
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Xiao Y, Zou X. Mathematical modeling and quantitative analysis of phenotypic plasticity during tumor evolution based on single-cell data. J Math Biol 2024; 89:34. [PMID: 39162836 DOI: 10.1007/s00285-024-02133-5] [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: 02/11/2024] [Revised: 06/24/2024] [Accepted: 08/08/2024] [Indexed: 08/21/2024]
Abstract
Tumor is a complex and aggressive type of disease that poses significant health challenges. Understanding the cellular mechanisms underlying its progression is crucial for developing effective treatments. In this study, we develop a novel mathematical framework to investigate the role of cellular plasticity and heterogeneity in tumor progression. By leveraging temporal single-cell data, we propose a reaction-convection-diffusion model that effectively captures the spatiotemporal dynamics of tumor cells and macrophages within the tumor microenvironment. Through theoretical analysis, we obtain the estimate of the pulse wave speed and analyze the stability of the homogeneous steady state solutions. Notably, we employe the AddModuleScore function to quantify cellular plasticity. One of the highlights of our approach is the introduction of pulse wave speed as a quantitative measure to precisely gauge the rate of cell phenotype transitions, as well as the novel implementation of the high-plasticity cell state/low-plasticity cell state ratio as an indicator of tumor malignancy. Furthermore, the bifurcation analysis reveals the complex dynamics of tumor cell populations. Our extensive analysis demonstrates that an increased rate of phenotype transition is associated with heightened malignancy, attributable to the tumor's ability to explore a wider phenotypic space. The study also investigates how the proliferation rate and the death rate of tumor cells, phenotypic convection velocity, and the midpoint of the phenotype transition stage affect the speed of tumor cell phenotype transitions and the progression to adenocarcinoma. These insights and quantitative measures can help guide the development of targeted therapeutic strategies to regulate cellular plasticity and control tumor progression effectively.
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Affiliation(s)
- Yuyang Xiao
- School of Mathematics and Statistics, Wuhan University, Wuhan, 430072, China
| | - Xiufen Zou
- School of Mathematics and Statistics, Wuhan University, Wuhan, 430072, China.
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11
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Audun Klingen T, Chen Y, Aas H, Akslen LA. DDR2 expression in breast cancer is associated with blood vessel invasion, basal-like tumors, tumor associated macrophages, regulatory T cells, detection mode and prognosis. Hum Pathol 2024; 150:29-35. [PMID: 38914168 DOI: 10.1016/j.humpath.2024.06.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/18/2024] [Accepted: 06/20/2024] [Indexed: 06/26/2024]
Abstract
Discoidin Domain Receptor 2 (DDR2) is a receptor tyrosine kinase for collagen, stimulating epithelial-mesenchymal transition and stiffness in breast cancer. Here, we investigated levels of DDR2 in breast tumor cells in relation to vascular invasion, TIL subsets, macrophages, molecular tumor subtypes, modes of detection and prognosis. This retrospective, population-based series of invasive breast carcinomas from the Norwegian Screening Program in Vestfold County (Norway), period 2004-2009, included 200 screening patients and 82 cases detected in screening intervals. DDR2 was examined on core needle biopsies using a semi-quantitative, immunohistochemical staining index and dichotomized as low or high DDR2 expression. Counts of macrophages and TIL subsets were dichotomized based on immunohistochemistry using TMA. We also recorded blood or lymphatic vessel invasion (BVI or LVI) as present or absent by immunohistochemistry. High expression of DDR2 in tumor cells showed significant relation with high counts of CD163+ macrophages (p < 0.001) and FOXP3 TILs (p = 0.011), presence of BVI (p = 0.028), high tumor cell proliferation by Ki67 (p = 0.033), ER negativity (p = 0.001), triple-negative cases (p = 0.038), basal-like features (p < 0.001) as well as interval detection (p < 0.001). By multivariate analysis, high DDR2 expression was related to reduced recurrence-free survival (HR, 2.3, p = 0.017), when examined together with histologic grading, lymph node assessment, tumor diameter, BVI, and molecular tumor subtype. This study supports a link between high DDR2 expression, high counts of macrophages by CD163 (tumor associated) and regulatory T cells by FOXP3 together with the presence of BVI, possibly indicating increased tumor motility and intravasation in aggressive breast tumors.
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MESH Headings
- Humans
- Female
- Breast Neoplasms/pathology
- Retrospective Studies
- Tumor-Associated Macrophages/immunology
- Tumor-Associated Macrophages/pathology
- Biomarkers, Tumor/analysis
- T-Lymphocytes, Regulatory/immunology
- T-Lymphocytes, Regulatory/pathology
- Neoplasm Invasiveness
- Middle Aged
- Immunohistochemistry
- Discoidin Domain Receptor 2
- Aged
- Lymphocytes, Tumor-Infiltrating/pathology
- Lymphocytes, Tumor-Infiltrating/immunology
- Norway
- Prognosis
- Receptors, Cell Surface/analysis
- Kaplan-Meier Estimate
- Antigens, CD
- Antigens, Differentiation, Myelomonocytic/analysis
- Antigens, Differentiation, Myelomonocytic/metabolism
- Biopsy, Large-Core Needle
- Proportional Hazards Models
- Predictive Value of Tests
- Forkhead Transcription Factors/analysis
- Macrophages/pathology
- Tumor Microenvironment
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Affiliation(s)
- Tor Audun Klingen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, Vestfold Hospital Trust, Norway.
| | - Ying Chen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of pathology, Fürst Medical Laboratory, Norway.
| | - Hans Aas
- Department of Surgery, Vestfold Hospital Trust, Norway.
| | - Lars A Akslen
- Centre for Cancer Biomarkers CCBIO, Department of Clinical Medicine, University of Bergen, Norway; Department of Pathology, Haukeland University Hospital, Norway.
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12
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Xiong H, Liao M, Zhang H, Li Y, Bai J, Zhang J, Li L, Zhang L. DARS expression in BCR/ABL1-negative myeloproliferative neoplasms and its association with the immune microenvironment. Sci Rep 2024; 14:16711. [PMID: 39030308 PMCID: PMC11271514 DOI: 10.1038/s41598-024-67067-w] [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: 04/15/2024] [Accepted: 07/08/2024] [Indexed: 07/21/2024] Open
Abstract
DARS, encoding for aspartyl-tRNA synthetase, is implicated in the pathogenesis of various cancers, including renal cell carcinoma, glioblastoma, colon cancer, and gastric cancer. Its role in BCR/ABL1-negative myeloproliferative neoplasms (MPNs), however, remains unexplored. This study aimed to elucidate the expression of DARS in patients with MPNs (PV 23, ET 19, PMF 16) through immunohistochemical analysis and to examine the profiles of circulating immune cells and cytokines using flow cytometry. Our findings indicate a significant overexpression of DARS in all MPNs subtypes at the protein level compared to controls (P < 0.05). Notably, elevated DARS expression was linked to splenomegaly in MPNs patients. The expression of DARS showed a negative correlation with CD4+ T cells (R = - 0.451, P = 0.0004) and CD4+ T/CD8+ T cell ratio (R = - 0.3758, P = 0.0040), as well as with CD68+ tumor-associated macrophages (R = 0.4037, P = 0.0017). Conversely, it was positively correlated with IL-2 (R = 0.5419, P < 0.001), IL-5 (R = 0.3161, P = 0.0166), IL-6 (R = 0.2992, P = 0.0238), and IFN-γ (R = 0.3873, P = 0.0029). These findings underscore a significant association between DARS expression in MPNs patients and specific clinical characteristics, as well as immune cell composition. Further investigation into the interplay between DARS and the immune microenvironment in MPNs could shed light on the underlying mechanisms of MPNs pathogenesis and immune dysregulation.
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Affiliation(s)
- Hao Xiong
- Department of Hematology, The Second Hospital of Lanzhou University, Lanzhou, China
- Stem Cell Immunity and Regeneration Key Laboratory of Luzhou, The Affiliated Hospital, Southwest Medical University, Luzhou, China
| | - Minjing Liao
- Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Huitao Zhang
- Department of General Practice, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Yanhong Li
- Department of Hematology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Jun Bai
- Department of Hematology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Jinping Zhang
- Department of Hematology, The Second Hospital of Lanzhou University, Lanzhou, China
| | - Lijuan Li
- Department of Hematology, The Second Hospital of Lanzhou University, Lanzhou, China.
| | - Liansheng Zhang
- Department of Hematology, The Second Hospital of Lanzhou University, Lanzhou, China.
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13
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Ten A, Kumeiko V, Farniev V, Gao H, Shevtsov M. Tumor Microenvironment Modulation by Cancer-Derived Extracellular Vesicles. Cells 2024; 13:682. [PMID: 38667297 PMCID: PMC11049026 DOI: 10.3390/cells13080682] [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: 02/11/2024] [Revised: 04/06/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
The tumor microenvironment (TME) plays an important role in the process of tumorigenesis, regulating the growth, metabolism, proliferation, and invasion of cancer cells, as well as contributing to tumor resistance to the conventional chemoradiotherapies. Several types of cells with relatively stable phenotypes have been identified within the TME, including cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), neutrophils, and natural killer (NK) cells, which have been shown to modulate cancer cell proliferation, metastasis, and interaction with the immune system, thus promoting tumor heterogeneity. Growing evidence suggests that tumor-cell-derived extracellular vesicles (EVs), via the transfer of various molecules (e.g., RNA, proteins, peptides, and lipids), play a pivotal role in the transformation of normal cells in the TME into their tumor-associated protumorigenic counterparts. This review article focuses on the functions of EVs in the modulation of the TME with a view to how exosomes contribute to the transformation of normal cells, as well as their importance for cancer diagnosis and therapy.
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Affiliation(s)
- Artem Ten
- School of Medicine and Life Sciences, Far Eastern Federal University, 690922 Vladivostok, Russia; (A.T.); (V.K.); (V.F.)
| | - Vadim Kumeiko
- School of Medicine and Life Sciences, Far Eastern Federal University, 690922 Vladivostok, Russia; (A.T.); (V.K.); (V.F.)
| | - Vladislav Farniev
- School of Medicine and Life Sciences, Far Eastern Federal University, 690922 Vladivostok, Russia; (A.T.); (V.K.); (V.F.)
| | - Huile Gao
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610064, China;
| | - Maxim Shevtsov
- School of Medicine and Life Sciences, Far Eastern Federal University, 690922 Vladivostok, Russia; (A.T.); (V.K.); (V.F.)
- Laboratory of Biomedical Nanotechnologies, Institute of Cytology of the Russian Academy of Sciences, Tikhoretsky Ave., 4, 194064 St. Petersburg, Russia
- Personalized Medicine Centre, Almazov National Medical Research Centre, Akkuratova Str., 2, 197341 St. Petersburg, Russia
- Department of Radiation Oncology, Technishe Universität München (TUM), Klinikum Rechts der Isar, Ismaninger Str., 22, 81675 Munich, Germany
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14
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Safaei S, Fadaee M, Farzam OR, Yari A, Poursaei E, Aslan C, Samemaleki S, Shanehbandi D, Baradaran B, Kazemi T. Exploring the dynamic interplay between exosomes and the immune tumor microenvironment: implications for breast cancer progression and therapeutic strategies. Breast Cancer Res 2024; 26:57. [PMID: 38553754 PMCID: PMC10981336 DOI: 10.1186/s13058-024-01810-z] [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: 10/31/2023] [Accepted: 03/18/2024] [Indexed: 04/01/2024] Open
Abstract
Breast cancer continues to pose a substantial worldwide health concern, demanding a thorough comprehension of the complex interaction between cancerous cells and the immune system. Recent studies have shown the significant function of exosomes in facilitating intercellular communication and their participation in the advancement of cancer. Tumor-derived exosomes have been identified as significant regulators in the context of breast cancer, playing a crucial role in modulating immune cell activity and contributing to the advancement of the illness. This study aims to investigate the many effects of tumor-derived exosomes on immune cells in the setting of breast cancer. Specifically, we will examine their role in influencing immune cell polarization, facilitating immunological evasion, and modifying the tumor microenvironment. Furthermore, we explore the nascent domain of exosomes produced from immune cells and their prospective involvement in the prevention of breast cancer. This paper focuses on new research that emphasizes the immunomodulatory characteristics of exosomes produced from immune cells. It also explores the possibility of these exosomes as therapeutic agents or biomarkers for the early identification and prevention of breast cancer. The exploration of the reciprocal connections between exosomes formed from tumors and immune cells, together with the rising significance of exosomes derived from immune cells, presents a potential avenue for the advancement of novel approaches in the field of breast cancer therapy and prevention.
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Affiliation(s)
- Sahar Safaei
- Immunology Research Center, Tabriz University of Medical Sciences, Gholghasht Ave, Tabriz, Iran
| | - Manouchehr Fadaee
- Immunology Research Center, Tabriz University of Medical Sciences, Gholghasht Ave, Tabriz, Iran
| | - Omid Rahbar Farzam
- Immunology Research Center, Tabriz University of Medical Sciences, Gholghasht Ave, Tabriz, Iran
| | - Amirhossein Yari
- Immunology Research Center, Tabriz University of Medical Sciences, Gholghasht Ave, Tabriz, Iran
- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
| | - Elham Poursaei
- Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Cynthia Aslan
- Research Center for Integrative Medicine in Aging, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Samemaleki
- Department of Immunology, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Gholghasht Ave, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Gholghasht Ave, Tabriz, Iran
| | - Tohid Kazemi
- Immunology Research Center, Tabriz University of Medical Sciences, Gholghasht Ave, Tabriz, Iran.
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15
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Zhang D, Huang H, Gao X, Yu G, Zhang X, Jin H, Xu R, Wang Z, Zhang G. High expression of B7-H3 on monocyte/macrophages in tumor microenvironment promotes lung cancer progression by inhibiting apoptosis. Transl Oncol 2024; 41:101874. [PMID: 38262113 PMCID: PMC10832491 DOI: 10.1016/j.tranon.2023.101874] [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: 10/16/2023] [Revised: 12/03/2023] [Accepted: 12/22/2023] [Indexed: 01/25/2024] Open
Abstract
Monocyte/macrophages constitute a significant population of tumor-infiltrating immune cells and play a crucial role in tumor growth, invasion, and metastasis. B7-H3, has immune regulatory functions, however, it is unclear whether B7-H3 expressed on monocyte/macrophages plays a significance role in tumor progression. We found B7-H3 was high-expressed on monocyte/macrophages in tumor microenvironment compared with adjacent tissues in lung cancer, and its expression level was positively correlated with the number of monocyte/macrophages. Furthermore, the expression of B7-H3 was related to clinical stage and lymph node metastasis. Moreover, miR-29a-3p negatively regulated B7-H3, and the expression of B7-H3 on THP-1-derived macrophages was regulated by secreting exosomes containing miR-29a-3p. In addition, knockdown of B7-H3 promoted macrophage apoptosis under hypoxia. Mechanistically, B7-H3 enhanced the antiapoptotic ability of macrophage by up-regulating HIF-1ɑ via activating NF-κB. Taken together, these results imply that B7-H3 as a therapeutic target could hold promise for enhancing anti-tumor immune responses in individuals diagnosed with lung cancer.
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Affiliation(s)
- Dongze Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Haitao Huang
- Department of Thoracic surgery, The First Affiliated Hospital of Soochow University, China
| | - Xin Gao
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, China
| | - Gehua Yu
- Department of Immunology, School of Biology and Basic Medical Sciences, Soochow University, China
| | - Xueguang Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Haiyan Jin
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Ruyan Xu
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China
| | - Zhenxin Wang
- Department of Medical Oncology, The First Affiliated Hospital of Soochow University, China.
| | - Guangbo Zhang
- Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, China.
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16
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Kotnala S, Dhasmana A, Dhasmana S, Haque S, Yallapu MM, Tripathi MK, Jaggi M, Chauhan SC. A Systems Biology Approach Unveils a Critical Role of DPP4 in Upper Gastrointestinal Cancer Patient Outcomes. J Environ Pathol Toxicol Oncol 2024; 43:43-55. [PMID: 38505912 PMCID: PMC11419273 DOI: 10.1615/jenvironpatholtoxicoloncol.2023048056] [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] [Indexed: 03/21/2024] Open
Abstract
Gastrointestinal (GI) cancers comprise of cancers that affect the digestive system and its accessory organs. The late detection and poor prognosis of GI cancer emphasizes the importance of identifying reliable and precise biomarkers for early diagnosis and prediction of prognosis. The membrane-bound glycoprotein dipeptidyl-peptidase 4 (DPP4), also known as CD26, is ubiquitously expressed and has a wide spectrum of biological roles. The role of DPP4/CD26 in tumor progression in different types of cancers remains elusive. However, the link between DPP4 and tumor-infiltrating cells, as well as its prognostic significance in malignancies, still require further investigation. This study was intended to elucidate the correlation of DPP4 expression and survival along with prognosis, followed by its associated enriched molecular pathways and immune cell marker levels in upper GI cancers. Results demonstrated a strong correlation between increased DPP4 expression and a worse prognosis in esophageal and gastric cancer and the co-expressed common genes with DPP4 were associated with crucial molecular pathways involved in tumorigenesis. Additionally, DPP4 was shown to be significantly linked to several immune infiltrating cell marker genes, including Macrophages (M1, M2 and Tumor Associated Macrophages), neutrophils, Treg, T-cell exhaustion, Th1 and Th2. Overall, our findings suggest that DPP4 may serve as a substantial prognostic biomarker, a possible therapeutic target, as well as it can play a critical role in the regulation of immune cell invasion in patients with gastroesophageal (esophageal, gastroesophageal junction and gastric) cancer. KEY WORDS: DPP4, integrated analysis, GI cancer, gastroesophageal cancer, gastroesophageal junction, prognosis.
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Affiliation(s)
- Sudhir Kotnala
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Anupam Dhasmana
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- Department of Biosciences and Cancer Research Institute, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Dehradun, India
| | - Swati Dhasmana
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Allied Health Sciences, Jazan University, Jazan, Saudi Arabia
- Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon
- Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates
| | - Murali M. Yallapu
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Manish K. Tripathi
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Meena Jaggi
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
| | - Subhash C. Chauhan
- Department of Immunology and Microbiology, School of Medicine, The University of Texas Rio Grande Valley, McAllen, TX 78504, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, TX 78504, USA
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17
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Misra G, Qaisar S, Singh P. CRISPR-based therapeutic targeting of signaling pathways in breast cancer. Biochim Biophys Acta Mol Basis Dis 2024; 1870:166872. [PMID: 37666438 DOI: 10.1016/j.bbadis.2023.166872] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Revised: 08/24/2023] [Accepted: 09/01/2023] [Indexed: 09/06/2023]
Abstract
Breast cancer remains a leading cause of death for women worldwide, and new treatment strategies are needed. There are innumerable anomalous genes that are responsible for the multi-factorial carcinogenesis pathway. Although several disease-causing mutations have been detected, therapy frequently focuses on attenuating the manifestation of the disease rather than harmonizing the mutation in the target area. The advent of CRISPR-Cas9 technology has revolutionized genome editing, allowing for precise and efficient manipulation of gene expression. The purpose of this review paper is to summarize recent progress in the use of CRISPR-based approaches to target key signaling pathways associated with breast cancer progression. The first section introduces basic concepts of CRISPR technology, focusing on its application in genome editing and transcriptional regulation followed by an overview of aspects involving complex signaling pathways in breast cancer such as P13K/AKT/mTOR, EPK/MAPK and Wnt/β catenin. An extensive literature search using PubMed and Google Scholar is performed for information retrieval. Further, the role of CRISPR-based interventions in regulating gene expression revealed, altered pathway activity and potential therapeutic consequences are discussed. This review will be a valuable addition to providing comprehensive knowledge of CRISPR-Cas-mediated therapeutic targeting in breast cancer.
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Affiliation(s)
- Gauri Misra
- National Institute of Biologicals, Noida 201309, UP, India.
| | - Sidra Qaisar
- National Institute of Biologicals, Noida 201309, UP, India
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18
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Schaer DJ, Schulthess-Lutz N, Baselgia L, Hansen K, Buzzi RM, Humar R, Dürst E, Vallelian F. Hemorrhage-activated NRF2 in tumor-associated macrophages drives cancer growth, invasion, and immunotherapy resistance. J Clin Invest 2023; 134:e174528. [PMID: 38060331 PMCID: PMC10849758 DOI: 10.1172/jci174528] [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: 08/07/2023] [Accepted: 11/28/2023] [Indexed: 02/02/2024] Open
Abstract
Microscopic hemorrhage is a common aspect of cancers, yet its potential role as an independent factor influencing both cancer progression and therapeutic response is largely ignored. Recognizing the essential function of macrophages in red blood cell disposal, we explored a pathway that connects intratumoral hemorrhage with the formation of cancer-promoting tumor-associated macrophages (TAMs). Using spatial transcriptomics, we found that NRF2-activated myeloid cells possessing characteristics of procancerous TAMs tend to cluster in perinecrotic hemorrhagic tumor regions. These cells resembled antiinflammatory erythrophagocytic macrophages. We identified heme, a red blood cell metabolite, as a pivotal microenvironmental factor steering macrophages toward protumorigenic activities. Single-cell RNA-Seq and functional assays of TAMs in 3D cell culture spheroids revealed how elevated intracellular heme signals via the transcription factor NRF2 to induce cancer-promoting TAMs. These TAMs stabilized epithelial-mesenchymal transition, enhancing cancer invasiveness and metastatic potential. Additionally, NRF2-activated macrophages exhibited resistance to reprogramming by IFN-γ and anti-CD40 antibodies, reducing their tumoricidal capacity. Furthermore, MC38 colon adenocarcinoma-bearing mice with NRF2 constitutively activated in leukocytes were resistant to anti-CD40 immunotherapy. Overall, our findings emphasize hemorrhage-activated NRF2 in TAMs as a driver of cancer progression, suggesting that targeting this pathway could offer new strategies to enhance cancer immunity and overcome therapy resistance.
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Huang J, Wu Q, Geller DA, Yan Y. Macrophage metabolism, phenotype, function, and therapy in hepatocellular carcinoma (HCC). J Transl Med 2023; 21:815. [PMID: 37968714 PMCID: PMC10652641 DOI: 10.1186/s12967-023-04716-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 11/09/2023] [Indexed: 11/17/2023] Open
Abstract
The pivotal role of the tumor microenvironment (TME) in the initiation and advancement of hepatocellular carcinoma (HCC) is widely acknowledged, as it fosters the proliferation and metastasis of HCC cells. Within the intricate TME of HCC, tumor-associated macrophages (TAMs) represent a significant constituent of non-malignant cells. TAMs engage in direct communication with cancer cells in HCC, while also exerting influence on other immune cells to adopt a tumor-supportive phenotype that facilitates tumor progression. Among the multifaceted mechanisms at play, the metabolic reprogramming of both tumor cells and macrophages leads to phenotypic alterations and functional modifications in macrophages. This comprehensive review elucidates the intricate interplay between cellular metabolism and macrophage phenotype/polarization, while also providing an overview of the associated signaling molecules and potential therapeutic strategies for HCC.
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Affiliation(s)
- Jingquan Huang
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China
| | - Qiulin Wu
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China
| | - David A Geller
- Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, 15260, USA.
| | - Yihe Yan
- Department of General Surgery, The Second Affiliated Hospital of Guangxi Medical University, Nanning, 530007, Guangxi, China.
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20
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Kumari A, Veena SM, Luha R, Tijore A. Mechanobiological Strategies to Augment Cancer Treatment. ACS OMEGA 2023; 8:42072-42085. [PMID: 38024751 PMCID: PMC10652740 DOI: 10.1021/acsomega.3c06451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023]
Abstract
Cancer cells exhibit aberrant extracellular matrix mechanosensing due to the altered expression of mechanosensory cytoskeletal proteins. Such aberrant mechanosensing of the tumor microenvironment (TME) by cancer cells is associated with disease development and progression. In addition, recent studies show that such mechanosensing changes the mechanobiological properties of cells, and in turn cells become susceptible to mechanical perturbations. Due to an increasing understanding of cell biomechanics and cellular machinery, several approaches have emerged to target the mechanobiological properties of cancer cells and cancer-associated cells to inhibit cancer growth and progression. In this Perspective, we summarize the progress in developing mechano-based approaches to target cancer by interfering with the cellular mechanosensing machinery and overall TME.
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Affiliation(s)
| | | | | | - Ajay Tijore
- Department of Bioengineering, Indian Institute of Science, Bangalore, Karnataka 560012, India
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21
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Chen L, Alabdullah M, Mahnke K. Adenosine, bridging chronic inflammation and tumor growth. Front Immunol 2023; 14:1258637. [PMID: 38022572 PMCID: PMC10643868 DOI: 10.3389/fimmu.2023.1258637] [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: 07/14/2023] [Accepted: 10/18/2023] [Indexed: 12/01/2023] Open
Abstract
Adenosine (Ado) is a well-known immunosuppressive agent that may be released or generated extracellularly by cells, via degrading ATP by the sequential actions of the ectonucleotides CD39 and CD73. During inflammation Ado is produced by leukocytes and tissue cells by different means to initiate the healing phase. Ado downregulates the activation and the effector functions of different leukocyte (sub-) populations and stimulates proliferation of fibroblasts for re-establishment of intact tissues. Therefore, the anti-inflammatory actions of Ado are already intrinsically triggered during each episode of inflammation. These tissue-regenerating and inflammation-tempering purposes of Ado can become counterproductive. In chronic inflammation, it is possible that Ado-driven anti-inflammatory actions sustain the inflammation and prevent the final clearance of the tissues from possible pathogens. These chronic infections are characterized by increased tissue damage, remodeling and accumulating DNA damage, and are thus prone for tumor formation. Developing tumors may further enhance immunosuppressive actions by producing Ado by themselves, or by "hijacking" CD39+/CD73+ cells that had already developed during chronic inflammation. This review describes different and mostly convergent mechanisms of how Ado-induced immune suppression, initially induced in inflammation, can lead to tumor formation and outgrowth.
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Affiliation(s)
| | | | - Karsten Mahnke
- Department of Dermatology, University Hospital Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany
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22
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Shevchenko JA, Nazarov KV, Alshevskaya AA, Sennikov SV. Erythroid Cells as Full Participants in the Tumor Microenvironment. Int J Mol Sci 2023; 24:15141. [PMID: 37894821 PMCID: PMC10606658 DOI: 10.3390/ijms242015141] [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: 09/12/2023] [Revised: 10/07/2023] [Accepted: 10/10/2023] [Indexed: 10/29/2023] Open
Abstract
The tumor microenvironment is an important factor that can determine the success or failure of antitumor therapy. Cells of hematopoietic origin are one of the most important mediators of the tumor-host interaction and, depending on the cell type and functional state, exert pro- or antitumor effects in the tumor microenvironment or in adjacent tissues. Erythroid cells can be full members of the tumor microenvironment and exhibit immunoregulatory properties. Tumor growth is accompanied by the need to obtain growth factors and oxygen, which stimulates the appearance of the foci of extramedullary erythropoiesis. Tumor cells create conditions to maintain the long-term proliferation and viability of erythroid cells. In turn, tumor erythroid cells have a number of mechanisms to suppress the antitumor immune response. This review considers current data on the existence of erythroid cells in the tumor microenvironment, formation of angiogenic clusters, and creation of optimal conditions for tumor growth. Despite being the most important life-support function of the body, erythroid cells support tumor growth and do not work against it. The study of various signaling mechanisms linking tumor growth with the mobilization of erythroid cells and the phenotypic and functional differences between erythroid cells of different origin allows us to identify potential targets for immunotherapy.
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Affiliation(s)
- Julia A. Shevchenko
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution, Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (J.A.S.); (K.V.N.)
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution, Ministry of Health of the Russian Federation, Higher Education I.M. Sechenov First Moscow State Medical University, Sechenov University, 119048 Moscow, Russia;
| | - Kirill V. Nazarov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution, Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (J.A.S.); (K.V.N.)
| | - Alina A. Alshevskaya
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution, Ministry of Health of the Russian Federation, Higher Education I.M. Sechenov First Moscow State Medical University, Sechenov University, 119048 Moscow, Russia;
| | - Sergey V. Sennikov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution, Research Institute of Fundamental and Clinical Immunology, 630099 Novosibirsk, Russia; (J.A.S.); (K.V.N.)
- Laboratory of Immune Engineering, Federal State Autonomous Educational Institution, Ministry of Health of the Russian Federation, Higher Education I.M. Sechenov First Moscow State Medical University, Sechenov University, 119048 Moscow, Russia;
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Guo W, Zhou B, Bie F, Huai Q, Xue X, Guo L, Tan F, Xue Q, Zhao L, Gao S. Single-cell RNA sequencing analysis reveals transcriptional heterogeneity of multiple primary lung cancer. Clin Transl Med 2023; 13:e1453. [PMID: 37846760 PMCID: PMC10580343 DOI: 10.1002/ctm2.1453] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Revised: 09/26/2023] [Accepted: 10/05/2023] [Indexed: 10/18/2023] Open
Abstract
INTRODUCTION With the advancements in early diagnosis, more and more patients with multiple primary lung cancer (MPLC) have been identified. However, the progression of MPLC involves complex changes in cell composition and metabolic function, which remains largely controversial. OBJECTIVE Our study aims to comprehensively reveal the cellular characteristics and inter-cellular connections of MPLC. METHODS We performed scRNA-seq from 23 samples of six MPLC patients, combined with bulk whole-exome sequencing. We performed trajectory analysis to investigate the transition of different cell types during the development of MPLC. RESULTS A total of 1 67 397 cells were sequenced derived from tumour and adjacent tissues of MPLC patients, and tumour, normal, immune and stromal cells were identified. Two states of epithelial cells were identified, which were associated with immune response and cell death, respectively. Furthermore, both CD8+ naïve and memory T cells participated in the differentiation of CD8+ T cells. The terminal states of CD8+ T cells were exhausted T cells and cytotoxic T cells, which positively regulated cell death and were implicated in the regulation of cytokine production, respectively. Two main subpopulations of B cells with distinct functions were identified, which participate in the regulation of the immune response and antigen presentation, respectively. In addition, we found a specific type of endothelial cells that were abundant in tumour samples, with an increasing trend from normal to tumour samples. CONCLUSIONS Our study showed the comprehensive landscape of different cells of MPLC, which might reveal the key cellular mechanisms and, therefore, may provide new insights into the early diagnosis and treatment of MPLC.
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Affiliation(s)
- Wei Guo
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
- Key Laboratory of Minimally Invasive Therapy Research for Lung CancerChinese Academy of Medical SciencesBeijingP. R. China
| | - Bolun Zhou
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Fenglong Bie
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
- Department of Thoracic SurgeryShandong Provincial Hospital Affiliated to Shandong First Medical UniversityJinanShandongP. R. China
| | - Qilin Huai
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Xuemin Xue
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Lei Guo
- Department of PathologyNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Fengwei Tan
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
- Key Laboratory of Minimally Invasive Therapy Research for Lung CancerChinese Academy of Medical SciencesBeijingP. R. China
| | - Qi Xue
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
- Key Laboratory of Minimally Invasive Therapy Research for Lung CancerChinese Academy of Medical SciencesBeijingP. R. China
| | - Liang Zhao
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
| | - Shugeng Gao
- Department of Thoracic SurgeryNational Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijingP. R. China
- Key Laboratory of Minimally Invasive Therapy Research for Lung CancerChinese Academy of Medical SciencesBeijingP. R. China
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Tan S, Wang Z, Li N, Guo X, Zhang Y, Ma H, Peng X, Zhao Y, Li C, Gao L, Li T, Liang X, Ma C. Transcription factor Zhx2 is a checkpoint that programs macrophage polarization and antitumor response. Cell Death Differ 2023; 30:2104-2119. [PMID: 37582865 PMCID: PMC10482862 DOI: 10.1038/s41418-023-01202-4] [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: 07/18/2022] [Revised: 07/22/2023] [Accepted: 08/02/2023] [Indexed: 08/17/2023] Open
Abstract
Macrophages are usually educated to tumor-associated macrophages (TAMs) in cancer with pro-tumor functions by tumor microenvironment (TME) and TAM reprogramming has been proposed as a potential tumor immunotherapy strategy. We recently demonstrated the critical role of Zinc-fingers and homeoboxes 2 (Zhx2) in macrophages' metabolic programming. However, whether Zhx2 is responsible for macrophage polarization and TAMs reprogramming is largely unknown. Here, we show that Zhx2 controls macrophage polarization under the inflammatory stimulus and TME. Myeloid-specific deletion of Zhx2 suppresses LPS-induced proinflammatory polarization but promotes IL-4 and TME-induced anti-inflammatory and pro-tumoral phenotypes in murine liver tumor models. Factors in TME, especially lactate, markedly decrease the expression of Zhx2 in TAMs, leading to the switch of TAMs to pro-tumor phenotype and consequent cancer progression. Notably, reduced ZHX2 expression in TAM correlates with poor survival of HCC patients. Mechanistic studies reveal that Zhx2 associates with NF-κB p65 and binds to the Irf1 promoter, leading to transcriptional activation of Irf1 in macrophages. Zhx2 functions in maintaining macrophage polarization by regulating Irf1 transcription, which may be a potential target for macrophage-based cancer immunotherapy.
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Affiliation(s)
- Siyu Tan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Zehua Wang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
- Department of Clinical Laboratory, Qilu Hospital, Shandong University (Qingdao), Qingdao, China
| | - Na Li
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Xiaowei Guo
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Yankun Zhang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Hongxin Ma
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
- Department of Clinical Laboratory, Shandong Cancer Hospital and Institute, Shandong First Medical University, and Shandong Academy of Medical Sciences, Jinan, China
| | - Xueqi Peng
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Ying Zhao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Chunyang Li
- Key Laboratory for Experimental Teratology of Ministry of Education, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Lifen Gao
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Xiaohong Liang
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China.
| | - Chunhong Ma
- Key Laboratory for Experimental Teratology of Ministry of Education, Key Laboratory of Infection and Immunity of Shandong Province and Department of Immunology, School of Basic Medical Sciences, Qilu Hospital, Cheeloo Medical College of Shandong University, Jinan, Shandong, China.
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Fernando V, Zheng X, Sharma V, Furuta S. Reprogramming of breast tumor-associated macrophages with modulation of arginine metabolism. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.22.554238. [PMID: 37662241 PMCID: PMC10473631 DOI: 10.1101/2023.08.22.554238] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
HER2+ breast tumors have abundant immune-suppressive cells, including M2-type tumor associated macrophages (TAMs). While TAMs consist of the immune-stimulatory M1-type and immune-suppressive M2-type, M1/M2-TAM ratio is reduced in immune-suppressive tumors, contributing to their immunotherapy refractoriness. M1 vs. M2-TAM formation depends on differential arginine metabolism, where M1-TAMs convert arginine to nitric oxide (NO) and M2-TAMs convert arginine to polyamines (PAs). We hypothesize that such distinct arginine metabolism in M1- vs M2-TAMs is attributed to different availability of BH4 (NO synthase cofactor) and that its replenishment would reprogram M2-TAMs to M1-TAMs. Recently, we reported that sepiapterin (SEP), the endogenous BH4 precursor, elevates the expression of M1-TAM markers within HER2+ tumors. Here, we show that SEP restores BH4 levels in M2-TAMs, which then redirects arginine metabolism to NO synthesis and converts M2-TAMs to M1-TAMs. The reprogrammed TAMs exhibit full-fledged capabilities of antigen presentation and induction of effector T cells to trigger immunogenic cell death of HER2+ cancer cells. This study substantiates the utility of SEP in metabolic shift of HER2+ breast tumor microenvironment as a novel immunotherapeutic strategy.
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Affiliation(s)
- Veani Fernando
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
- Division of Rheumatology, University of Colorado, Anschutz Medical Campus Barbara Davis Center, Mail Stop B115, 1775 Aurora Court, Aurora, Colorado 80045
| | - Xunzhen Zheng
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
| | - Vandana Sharma
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
| | - Saori Furuta
- Department of Cell & Cancer Biology, College of Medicine and Life Sciences, University of Toledo Health Science Campus, 3000 Arlington Ave. Toledo, OH 43614, USA
- MetroHealth Medical Center, Case Western Reserve University School of Medicine, Case Comprehensive Cancer Center, 2500 MetroHealth Drive, Cleveland, OH 44109
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Li ML, Hong XX, Zhang WJ, Liang YZ, Cai TT, Xu YF, Pan HF, Kang JY, Guo SJ, Li HW. Helicobacter pylori plays a key role in gastric adenocarcinoma induced by spasmolytic polypeptide-expressing metaplasia. World J Clin Cases 2023; 11:3714-3724. [PMID: 37383139 PMCID: PMC10294147 DOI: 10.12998/wjcc.v11.i16.3714] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 03/01/2023] [Accepted: 04/23/2023] [Indexed: 06/02/2023] Open
Abstract
Heliobacter pylori (H. pylori), a group 1 human gastric carcinogen, is significantly associated with chronic gastritis, gastric mucosal atrophy, and gastric cancer. Approximately 20% of patients infected with H. pylori develop precancerous lesions, among which metaplasia is the most critical. Except for intestinal metaplasia (IM), which is characterized by goblet cells appearing in the stomach glands, one type of mucous cell metaplasia, spasmolytic polypeptide-expressing metaplasia (SPEM), has attracted much attention. Epidemiological and clinicopathological studies suggest that SPEM may be more strongly linked to gastric adenocarcinoma than IM. SPEM, characterized by abnormal expression of trefoil factor 2, mucin 6, and Griffonia simplicifolia lectin II in the deep glands of the stomach, is caused by acute injury or inflammation. Although it is generally believed that the loss of parietal cells alone is a sufficient and direct cause of SPEM, further in-depth studies have revealed the critical role of immunosignals. There is controversy regarding whether SPEM cells originate from the transdifferentiation of mature chief cells or professional progenitors. SPEM plays a functional role in the repair of gastric epithelial injury. However, chronic inflammation and immune responses caused by H. pylori infection can induce further progression of SPEM to IM, dysplasia, and adenocarcinoma. SPEM cells upregulate the expression of whey acidic protein 4-disulfide core domain protein 2 and CD44 variant 9, which recruit M2 macrophages to the wound. Studies have revealed that interleukin-33, the most significantly upregulated cytokine in macrophages, promotes SPEM toward more advanced metaplasia. Overall, more effort is needed to reveal the specific mechanism of SPEM malignant progression driven by H. pylori infection.
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Affiliation(s)
- Mian-Li Li
- Department of Gastroenterology, Shenzhen Hospital of Integrated, Traditional Chinese and Western Medicine, Shenzhen 518033, Guangdong Province, China
| | - Xin-Xin Hong
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Wei-Jian Zhang
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Yi-Zhong Liang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Tian-Tian Cai
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Yi-Fei Xu
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hua-Feng Pan
- Science and Technology Innovation Center, Guangzhou University of Traditional Chinese Medicine, Guangzhou 510405, Guangdong Province, China
| | - Jian-Yuan Kang
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Shao-Ju Guo
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
| | - Hai-Wen Li
- Department of Gastroenterology, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong Province, China
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Xu G, Mo Y, Li J, Wei Q, Zhou F, Chen J. Two tripartite classification systems of CD86 + and CD206 + macrophages are significantly associated with tumor recurrence in stage II-III colorectal cancer. Front Immunol 2023; 14:1136875. [PMID: 37342343 PMCID: PMC10277500 DOI: 10.3389/fimmu.2023.1136875] [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: 01/03/2023] [Accepted: 05/22/2023] [Indexed: 06/22/2023] Open
Abstract
Introduction The prognostic value of tumor-associated macrophages remains unclear in colorectal cancer (CRC). Two tripartite classification systems, namely, ratio and quantity subgroups, were investigated as the prognostic stratification tools for stage II-III CRC. Methods We assessed the infiltration intensity of CD86+ and CD206+ macrophages in 449 cases with stage II-III disease by immunohistochemical staining. Ratio subgroups were defined by the lower- and upper-quartile points of CD206+/(CD86++CD206+) macrophage ratio, including the low-, moderate-, and high-ratio subgroups. Quantity subgroups were defined by the median points of CD86+ and CD206+ macrophages and included the low-, moderate-, and high-risk subgroups. The main analysis was recurrence-free survival (RFS) and overall survival (OS). Results Ratio subgroups (RFS/OS: HR=2.677/2.708, all p<0.001) and quantity subgroups (RFS/OS: HR=3.137/3.250, all p<0.001) could serve as independent prognostic indicators that effectively predicted survival outcomes. More importantly, log-rank test revealed that patients in the high-ratio (RFS/OS: HR=2.950/3.151, all p<0.001) or high-risk (RFS/OS: HR=3.453/3.711, all p<0.001) subgroup exhibited decreased survival outcomes after adjuvant chemotherapy. The predictive accuracy of the quantity subgroups within 48 months was higher than that of the ratio subgroups and tumor stage (all p<0.05). Conclusions Ratio and quantity subgroups could serve as independent prognostic indicators that could potentially be incorporated into the tumor staging algorithm to improve prognostic stratification and provide better predictions of survival outcomes in stage II-III CRC after adjuvant chemotherapy.
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Affiliation(s)
- Guozeng Xu
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei, China
- Department of Oncology, Liuzhou People’s Hospital of Guangxi Medical University, Guangxi, China
| | - Yuzhen Mo
- Department of Radiation Oncology, Guangzhou Red Cross Hospital of Jinan University, Guangdong, China
| | - Jing Li
- Department of Oncology, Liuzhou People’s Hospital of Guangxi Medical University, Guangxi, China
| | - Qingqing Wei
- Department of Oncology, Liuzhou People’s Hospital of Guangxi Medical University, Guangxi, China
| | - Fuxiang Zhou
- Department of Radiation and Medical Oncology, Zhongnan Hospital of Wuhan University, Hubei, China
| | - Jian Chen
- Department of Medical Oncology, Yantai Yuhuangding Hospital of Qingdao University, Shandong, China
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Liu J, Zhang M, Sun Q, Qin X, Gao T, Xu Y, Han S, Zhang Y, Guo Z. Construction of a novel MPT-driven necrosis-related lncRNAs signature for prognosis prediction in laryngeal squamous cell carcinoma. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023:10.1007/s11356-023-26996-1. [PMID: 37249774 DOI: 10.1007/s11356-023-26996-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 04/09/2023] [Indexed: 05/31/2023]
Abstract
Mitochondrial permeability transition (MPT)-driven necrosis, a type of programmed cell death, has recently gained much attention in a variety of tumor types. Few studies have been performed to explore the role of MPT-driven necrosis-related lncRNAs (MPTDNRlncRNAs) in laryngeal squamous cell carcinoma (LSCC). The purpose of our study is to screen MPTDNRlncRNAs with prognostic value and to explore their potential roles in LSCC. The RNA-sequencing data and the corresponding clinical data of LSCC patients were obtained from the TCGA database, and those MPT-driven necrosis-related genes were extracted from the Gene Set Enrichment Analysis (GSEA) database. We identified MPTDNRlncRNAs differentially expressed in LSCC. Also, we gained MPT-driven necrosis-related prognostic lncRNAs by univariate cox regression analysis. A novel MPTDNRlncRNAs signature was constructed by LASSO-COX. The accuracy and utility of the MPTDNRlncRNAs signature were evaluated via a variety of statistical methods. Multiple bioinformatics tools were used to explore the underlying difference in biological functions and signaling pathways between the different risk groups. The expressions levels of MPTDNRlncRNAs were analyzed using RT-qPCR in LSCC cell line. Finally, we identified A 5 MPTDNRlncRNAs signature in LSCC. Our prognostic model demonstrated an efficient ability to predict outcomes. The proportion difference of immune cells in the subgroups were significant, such as M0 macrophage and T follicular helper cells. The in vitro experiments suggested that our MPTDNRlncRNAs were significantly different. This 5 MPTDNRlncRNAs signature is a prognostic biomarker for LSCC. More importantly, the novel biologic prognostic model can be utilized for personalized immunotherapy in LSCC patients.
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Affiliation(s)
- Jian Liu
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China
| | - Min Zhang
- Xiangya Hospital, Central South University, Changsha, Hunan, 41000, People's Republic of China
| | - Qing Sun
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China
| | - Xuemei Qin
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China
| | - Tianle Gao
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China
| | - Yinwei Xu
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China
| | - Shuhui Han
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China
| | - Yujie Zhang
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China
| | - Zhiqiang Guo
- Department of Otolaryngology-Head and Neck Surgery, QingPu Branch of Zhongshan Affilated to Fudan University, Shanghai, 201700, People's Republic of China.
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(Stămat) LRB, Dinescu S, Costache M. Regulation of Inflammasome by microRNAs in Triple-Negative Breast Cancer: New Opportunities for Therapy. Int J Mol Sci 2023; 24:ijms24043245. [PMID: 36834660 PMCID: PMC9963301 DOI: 10.3390/ijms24043245] [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: 12/21/2022] [Revised: 01/28/2023] [Accepted: 02/02/2023] [Indexed: 02/09/2023] Open
Abstract
During the past decade, researchers have investigated the molecular mechanisms of breast cancer initiation and progression, especially triple-negative breast cancer (TNBC), in order to identify specific biomarkers that could serve as feasible targets for innovative therapeutic strategies development. TNBC is characterized by a dynamic and aggressive nature, due to the absence of estrogen, progesterone and human epidermal growth factor 2 receptors. TNBC progression is associated with the dysregulation of nucleotide-binding oligomerization domain-like receptor and pyrin domain-containing protein 3 (NLRP3) inflammasome, followed by the release of pro-inflammatory cytokines and caspase-1 dependent cell death, termed pyroptosis. The heterogeneity of the breast tumor microenvironment triggers the interest of non-coding RNAs' involvement in NLRP3 inflammasome assembly, TNBC progression and metastasis. Non-coding RNAs are paramount regulators of carcinogenesis and inflammasome pathways, which could help in the development of efficient treatments. This review aims to highlight the contribution of non-coding RNAs that support inflammasome activation and TNBC progression, pointing up their potential for clinical applications as biomarkers for diagnosis and therapy.
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Affiliation(s)
| | - Sorina Dinescu
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania
- Research Institute of the University of Bucharest, 050663 Bucharest, Romania
- Correspondence:
| | - Marieta Costache
- Department of Biochemistry and Molecular Biology, University of Bucharest, 050095 Bucharest, Romania
- Research Institute of the University of Bucharest, 050663 Bucharest, Romania
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The Tumor Microenvironment in Tumorigenesis and Therapy Resistance Revisited. Cancers (Basel) 2023; 15:cancers15020376. [PMID: 36672326 PMCID: PMC9856874 DOI: 10.3390/cancers15020376] [Citation(s) in RCA: 76] [Impact Index Per Article: 38.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/28/2022] [Accepted: 01/04/2023] [Indexed: 01/09/2023] Open
Abstract
Tumorigenesis is a complex and dynamic process involving cell-cell and cell-extracellular matrix (ECM) interactions that allow tumor cell growth, drug resistance and metastasis. This review provides an updated summary of the role played by the tumor microenvironment (TME) components and hypoxia in tumorigenesis, and highlight various ways through which tumor cells reprogram normal cells into phenotypes that are pro-tumorigenic, including cancer associated- fibroblasts, -macrophages and -endothelial cells. Tumor cells secrete numerous factors leading to the transformation of a previously anti-tumorigenic environment into a pro-tumorigenic environment. Once formed, solid tumors continue to interact with various stromal cells, including local and infiltrating fibroblasts, macrophages, mesenchymal stem cells, endothelial cells, pericytes, and secreted factors and the ECM within the tumor microenvironment (TME). The TME is key to tumorigenesis, drug response and treatment outcome. Importantly, stromal cells and secreted factors can initially be anti-tumorigenic, but over time promote tumorigenesis and induce therapy resistance. To counter hypoxia, increased angiogenesis leads to the formation of new vascular networks in order to actively promote and sustain tumor growth via the supply of oxygen and nutrients, whilst removing metabolic waste. Angiogenic vascular network formation aid in tumor cell metastatic dissemination. Successful tumor treatment and novel drug development require the identification and therapeutic targeting of pro-tumorigenic components of the TME including cancer-associated- fibroblasts (CAFs) and -macrophages (CAMs), hypoxia, blocking ECM-receptor interactions, in addition to the targeting of tumor cells. The reprogramming of stromal cells and the immune response to be anti-tumorigenic is key to therapeutic success. Lastly, this review highlights potential TME- and hypoxia-centered therapies under investigation.
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Mendes AS, Romão R, Febra J, Azevedo SX, Fidalgo P, Araújo A. Chemotherapy: A partnership with immunotherapy in non-small cell lung cancer. Thorac Cancer 2022; 14:437-441. [PMID: 36539276 PMCID: PMC9925346 DOI: 10.1111/1759-7714.14779] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/07/2022] [Accepted: 12/08/2022] [Indexed: 02/15/2023] Open
Abstract
Chemotherapy (CT) and immunotherapy (IO) act synergically in the treatment of non-small cell lung cancer (NSCLC). However, the molecular basis of such interaction is poorly understood. The aim of this review was to explore the mechanisms of CT to potentiate the immune system and, consequently, the action of IO. The most up-to-date knowledge concerning the interaction of CT and IO in NSCLC was reviewed and a bibliographic search was made in PubMed/Medline database, using the mentioned keywords, with preference given to recently published articles in English. In addition to the direct cytotoxic effect, CT affects the immune system leading indirectly to cell death. The immune response triggered by PD-1 inhibition is enhanced by the cytotoxic immunogenic effects of CT. This potentiation phenomenon occurs due to an increase in effector cells relatively to regulatory cells, inhibition of myeloid derived suppressor cells, increased potential for cross-presentation by dendritic cells after the death of tumor cells or blocking the STAT6 pathway to increase dendritic cell activity. In conclusion, the effects of CT on the immune system work in synergy with the actions of IO, transforming "cold" tumors into "hot" tumors, which are more visible to the immune system.
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Affiliation(s)
- Ana Sofia Mendes
- Medical Oncology DepartmentCentro Hospitalar Universitário do PortoPortugal
| | - Raquel Romão
- Medical Oncology DepartmentCentro Hospitalar Universitário do PortoPortugal
| | - Joana Febra
- Medical Oncology DepartmentCentro Hospitalar Universitário do PortoPortugal
| | | | - Paula Fidalgo
- Medical Oncology DepartmentCentro Hospitalar Universitário do PortoPortugal
| | - António Araújo
- Medical Oncology DepartmentCentro Hospitalar Universitário do PortoPortugal,Oncology Research Unit, UMIB—Unit for Multidisciplinary Research in Biomedicine, ICBAS ‐ School of Medicine and Biomedical Sciences, Universidade do Porto
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Functional differences between primary monocyte-derived and THP-1 macrophages and their response to LCPUFAs. PHARMANUTRITION 2022. [DOI: 10.1016/j.phanu.2022.100322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Zhang G, Guo F, Zeng M, Wang Z, Qin F, Chen J, Zheng Z, He Z. The immune-enhancing effect and in vitro antioxidant ability of different fractions separated from Colla corii asini. J Food Biochem 2022; 46:e14174. [PMID: 35415887 DOI: 10.1111/jfbc.14174] [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: 11/30/2021] [Revised: 03/01/2022] [Accepted: 03/28/2022] [Indexed: 12/29/2022]
Abstract
In this study, Colla corii asini (CCA) was fractionated into three fractions with different molecular weights using ultracentrifugation equipment. Components with a molecular weight of >10 kDa in F1 accounted for 81.90%, whereas that in F2 and F3 was 15.63% and 0.94%, respectively. The immunomodulatory activity of CCA fractions was investigated using RAW264.7 cell model and their antioxidant abilities were evaluated by 2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) (ABTS) and ferric-reducing antioxidant power (FRAP) assay. The results indicated that RAW264.7 cells treated with F1 released the highest level of nitric oxide, reactive oxygen species, interleukin-6, and tumor necrosis factor-α. The ABTS and FRAP value of F1 were 65.81% and 29.33 μM TE/L, respectively, which were 22.53%, 128.44% and 43.72%, 132.16% higher than that of F2 and F3, respectively. These results suggested that components with a molecular weight of >10 kDa in CCA had stronger immunomodulatory and antioxidant ability, which would help develop the health food based on CCA. PRACTICAL APPLICATIONS: Colla corii asini (CCA) is a famous protein-based traditional Chinese medicine and nutritional supplement. During the processing of CCA, the molecular weight (MW) of CCA collagen components changed dynamically due to the protein aggregation, degradation, and the Maillard reaction. Some studies have shown that the MW distribution of CCA was not uniform. However, the MW range of CCA components which has strong antioxidant and immunomodulatory activity is still not clear, and few studies have reported the mechanism of CCA's immunomodulatory activity and active ingredients. Therefore, it is important to figure out the characteristics of CCA components with stronger immunomodulatory and antioxidant ability, such as the MW distribution and chemical composition of CCA fractions. And this study will be great for the processing of CCA products which has better biological functions.
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Affiliation(s)
- Guowei Zhang
- Fujian Province Key Laboratory for the Development of Bioactive Material from Marine Algae, Quanzhou Normal University, Quanzhou, China.,State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Fengxian Guo
- Fujian Province Key Laboratory for the Development of Bioactive Material from Marine Algae, Quanzhou Normal University, Quanzhou, China
| | - Maomao Zeng
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Zhaojun Wang
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Fang Qin
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Jie Chen
- State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
| | - Zongping Zheng
- Fujian Province Key Laboratory for the Development of Bioactive Material from Marine Algae, Quanzhou Normal University, Quanzhou, China
| | - Zhiyong He
- Fujian Province Key Laboratory for the Development of Bioactive Material from Marine Algae, Quanzhou Normal University, Quanzhou, China.,State Key Laboratory of Food Science and Technology, Jiangnan University, Wuxi, China
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Ou Z, Lin S, Qiu J, Ding W, Ren P, Chen D, Wang J, Tong Y, Wu D, Chen A, Deng Y, Cheng M, Peng T, Lu H, Yang H, Wang J, Jin X, Ma D, Xu X, Wang Y, Li J, Wu P. Single-Nucleus RNA Sequencing and Spatial Transcriptomics Reveal the Immunological Microenvironment of Cervical Squamous Cell Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2203040. [PMID: 35986392 PMCID: PMC9561780 DOI: 10.1002/advs.202203040] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 07/10/2022] [Indexed: 05/07/2023]
Abstract
The effective treatment of advanced cervical cancer remains challenging. Herein, single-nucleus RNA sequencing (snRNA-seq) and SpaTial enhanced resolution omics-sequencing (Stereo-seq) are used to investigate the immunological microenvironment of cervical squamous cell carcinoma (CSCC). The expression levels of most immune suppressive genes in the tumor and inflammation areas of CSCC are not significantly higher than those in the non-cancer samples, except for LGALS9 and IDO1. Stronger signals of CD56+ NK cells and immature dendritic cells are found in the hypermetabolic tumor areas, whereas more eosinophils, immature B cells, and Treg cells are found in the hypometabolic tumor areas. Moreover, a cluster of pro-tumorigenic cancer-associated myofibroblasts (myCAFs) are identified. The myCAFs may support the growth and metastasis of tumors by inhibiting lymphocyte infiltration and remodeling of the tumor extracellular matrix. Furthermore, these myCAFs are associated with poorer survival probability in patients with CSCC, predict resistance to immunotherapy, and might be present in a small fraction (< 30%) of patients with advanced cancer. Immunohistochemistry and multiplex immunofluorescence staining are conducted to validate the spatial distribution and potential function of myCAFs. Collectively, these findings enhance the understanding of the immunological microenvironment of CSCC and shed light on the treatment of advanced CSCC.
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Rangel-Pozzo A, Wechsler J, Groult J, Da Meda L, Lebbe C, Mai S. Telomere-Associated Changes in Nuclear Architecture of Cancer-Associated Macrophage-like Cells in Liquid Biopsies from Melanoma Patients. Biomedicines 2022; 10:biomedicines10102391. [PMID: 36289653 PMCID: PMC9598704 DOI: 10.3390/biomedicines10102391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/16/2022] [Accepted: 09/21/2022] [Indexed: 11/16/2022] Open
Abstract
During phagocytosis, tumor-associated macrophages (TAMs) can incorporate genetic material from tumor cells. The incorporation of extra genetic material may be responsible for advanced malignant behavior observed in some TAMs, making TAMs potentially important players in cancer progression. More recently, similar cells were described in the blood as cancer-associated macrophage-like cells (CAMLs). CAMLs may be equivalent to TAMs cells in the blood, and they express macrophage markers. However, their origin is still unclear. In a previous study, we showed for the first time the distinct telomere 3D structure of circulating tumor cells (CTCs) in melanoma and other cancers. In the present pilot study, we investigated, comparatively, the 3D telomere structure of CAMLs, CTCs and leucocytes from nine melanoma patients with metastatic cutaneous melanoma stage IV. CTC capture was performed by size-based filtration followed by cytological and immunocytological evaluation. Three-dimensional Quantitative Fluorescent in situ Hybridization was performed to measure differences in five 3D telomere parameters. Telomere parameters, such as number, length, telomere aggregates, nuclear volume, and a/c ratio, were compared among different cellular types (CTCs, CAMLs, and normal leucocytes). Three telomere parameters were significantly different between CAMLs and leucocytes. The combination of two telomere parameters (telomere length against the number of telomeres) resulted in the identification of two CAMLs subpopulations with different levels of genomic instability. Those populations were classified as profile 1 and 2. Profile 2, characterized by a high number of short telomeres, was observed in four of the nine melanoma patients. To our knowledge, this is the first pilot study to investigate 3D telomere parameters as hallmarks of nuclear architecture in CAMLs’ population in comparison to leucocytes from the same patient. Further studies involving a larger patient sample size are necessary to validate these findings and explore their potential prognostic value.
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Affiliation(s)
- Aline Rangel-Pozzo
- CancerCare Manitoba Research Institute, University of Manitoba, Winnipeg, MB R3C 2B1, Canada
- Correspondence: (A.R.-P.); (S.M.); Tel.: +1-(204)-787-2135 (S.M.)
| | - Janine Wechsler
- Screencell Company, 62 rue de Wattignies, F-75012 Paris, France
| | - Jessica Groult
- Screencell Company, 62 rue de Wattignies, F-75012 Paris, France
| | - Laetitia Da Meda
- INSERM U976, Team 1, HIPI, Université de Paris, F-75010 Paris, France
- Service de Dermatologie, AP-HP Hôpital Saint Louis, F-75010 Paris, France
| | - Celeste Lebbe
- INSERM U976, Team 1, HIPI, Université de Paris, F-75010 Paris, France
- Service de Dermatologie, AP-HP Hôpital Saint Louis, F-75010 Paris, France
| | - Sabine Mai
- CancerCare Manitoba Research Institute, University of Manitoba, Winnipeg, MB R3C 2B1, Canada
- Correspondence: (A.R.-P.); (S.M.); Tel.: +1-(204)-787-2135 (S.M.)
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36
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Wei F, Guo R, Yan Y, Lin R, Chen J, Lin Z. Investigation of the efficacy and safety of cryoablation and intra-arterial PD-1 inhibitor in patients with advanced disease not responding to checkpoint inhibitors: An exploratory study. Front Immunol 2022; 13:990224. [PMID: 36211329 PMCID: PMC9537743 DOI: 10.3389/fimmu.2022.990224] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Accepted: 09/09/2022] [Indexed: 11/26/2022] Open
Abstract
Objective To explore the effectiveness of cryoablation combined with arterial perfusion with programmed cell death protein 1 inhibitors in overcoming immune resistance in advanced solid cancers. Methods In this pilot retrospective study, nine patients with solid cancers were treated with tumour cryoablation and arterial perfusion with programmed cell death protein 1 inhibitors, which had previously proven ineffective. The CIBERSORT software was used to estimate the levels of tumour-infiltrating immune cells in the challenged tumour. Changes in the levels of circulating T cells were assessed using flow cytometry. The primary endpoints were disease control and objective response rates, and the secondary endpoint was safety. Results The nine patients with advanced solid tumours received cryoablation combined with arterial perfusion with programmed cell death protein 1 inhibitors between June and December 2021. The median follow-up time was 5.8 months. We recorded an objective response rate in two patients (22.22%). The best overall responses were partial responses in two patients (22.22%) and one case (11.11%) of stable disease, while six patients (66.67%) presented progressive disease. However, the median overall survival time was not reached. The median progression-free survival was 2.4 months. Treatment-related severe adverse events included one case of abdominal infection and one case of upper gastrointestinal bleeding, which were cured after the intervention. The CIBERSORT software confirmed the importance of cryoablation in regulating tumour-infiltrating immune cells. Thus, macrophage polarisation from the M2 to the M1 phenotype in the challenged tumour and a gradual increase in the levels of circulating CD4+ T cells were observed after administration of the combination therapy. Conclusion Cryoablation combined with arterial perfusion with programmed cell death protein 1 inhibitors has the potential efficacy and safety to overcome immune resistance in patients with advanced solid cancers. The combination therapy leads to macrophage polarisation from the M2 to the M1 phenotype in the challenged tumour to enhance antitumour immunity.
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Affiliation(s)
- Fuqun Wei
- The Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Rui Guo
- The Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yuan Yan
- The Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Ruixiang Lin
- The Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Jin Chen
- The Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Zhengyu Lin
- The Department of Interventional Radiology, First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
- Fujian Provincial Key Laboratory of Precision Medicine for Cancer, Fuzhou, Fujian, China
- *Correspondence: Zhengyu Lin,
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CCL2 overexpression is associated with paclitaxel resistance in ovarian cancer cells via autocrine signaling and macrophage recruitment. Biomed Pharmacother 2022; 153:113474. [DOI: 10.1016/j.biopha.2022.113474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 07/15/2022] [Accepted: 07/23/2022] [Indexed: 11/17/2022] Open
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Parayath NN, Gandham SK, Amiji MM. Tumor-targeted miRNA nanomedicine for overcoming challenges in immunity and therapeutic resistance. Nanomedicine (Lond) 2022; 17:1355-1373. [PMID: 36255330 PMCID: PMC9706370 DOI: 10.2217/nnm-2022-0130] [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: 12/24/2022] Open
Abstract
miRNA are critical messengers in the tumor microenvironment (TME) that influence various processes leading to immune suppression, tumor progression, metastasis and resistance. Strategies to modulate miRNAs in the TME have important implications in overcoming these challenges. However, miR delivery to specific cells in the TME has been challenging. This review discusses nanomedicine strategies to achieve cell-specific delivery of miRNAs. The key goal of delivery is to activate the tumor immune landscape as well as to prevent chemotherapy resistance. Specifically, the use of hyaluronic acid-based nanoparticle miRNA delivery to the TME is discussed. The discussion is focused on miRNA-125b for reprogramming tumor-associated macrophages to overcome immunosuppression and miRNA-let-7b to overcome resistance to anticancer chemotherapeutics because both these miRNAs have been extensively evaluated for delivery with hyaluronic acid-based delivery systems.
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Affiliation(s)
- Neha N Parayath
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Srujan K Gandham
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Mansoor M Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA,Department of Chemical Engineering, College of Engineering, Northeastern University, Boston, MA 02115, USA,Author for correspondence: Tel.: +1 617 373 3137;
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Chen G, Cai Y, Li B, Lin M, Wang X, Wang Z, Shuai X. Theranostic nanosystem mediating cascade catalytic reactions for effective immunotherapy of highly immunosuppressive and poorly penetrable pancreatic tumor. Sci China Chem 2022. [DOI: 10.1007/s11426-022-1262-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Tajaldini M, Saeedi M, Amiriani T, Amiriani AH, Sedighi S, Mohammad Zadeh F, Dehghan M, Jahanshahi M, Zanjan Ghandian M, Khalili P, Poorkhani AH, Alizadeh AM, Khori V. Cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs); where do they stand in tumorigenesis and how they can change the face of cancer therapy? Eur J Pharmacol 2022; 928:175087. [PMID: 35679891 DOI: 10.1016/j.ejphar.2022.175087] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2022] [Revised: 05/18/2022] [Accepted: 06/03/2022] [Indexed: 11/03/2022]
Abstract
The tumor microenvironment (TME) and its components have recently attracted tremendous attention in cancer treatment strategies, as alongside the genetic and epigenetic alterations in tumor cells, TME could also provide a fertile background for malignant cells to survive and proliferate. Interestingly, TME plays a vital role in the mediation of cancer metastasis and drug resistance even against immunotherapeutic agents. Among different cells that are presenting in TME, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs) have shown to have significant value in the regulation of angiogenesis, tumor metastasis, and drug-resistance through manipulating the composition as well as the organization of extracellular matrix (ECM). Evidence has shown that the presence of both TAMs and CAFs in TME is associated with poor prognosis and failure of chemotherapeutic agents. It seems that these cells together with ECM form a shield around tumor cells to protect them from the toxic agents and even the adaptive arm of the immune system, which is responsible for tumor surveillance. Given this, targeting TAMs and CAFs seems to be an essential approach to potentiate the cytotoxic effects of anti-cancer agents, either conventional chemotherapeutic drugs or immunotherapies. In the present review, we aimed to take a deep look at the mechanobiology of CAFs and TAMs in tumor progression and to discuss the available therapeutic approaches for harnessing these cells in TME.
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Affiliation(s)
- Mahboubeh Tajaldini
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohsen Saeedi
- Stem Cell Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Taghi Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Amir Hossein Amiriani
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Sima Sedighi
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Fatemeh Mohammad Zadeh
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mohammad Dehghan
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Mehrdad Jahanshahi
- Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Maziar Zanjan Ghandian
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | - Pedram Khalili
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran
| | | | - Ali Mohammad Alizadeh
- Cancer Research Center, Cancer Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Vahid Khori
- Ischemic Disorder Research Center, Golestan University of Medical Sciences, Gorgan, Iran.
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Gilbertie JM, Schaer TP, Engiles JB, Seiler GS, Deddens BL, Schubert AG, Jacob ME, Stefanovski D, Ruthel G, Hickok NJ, Stowe DM, Frink A, Schnabel LV. A Platelet-Rich Plasma-Derived Biologic Clears Staphylococcus aureus Biofilms While Mitigating Cartilage Degeneration and Joint Inflammation in a Clinically Relevant Large Animal Infectious Arthritis Model. Front Cell Infect Microbiol 2022; 12:895022. [PMID: 35711655 PMCID: PMC9195519 DOI: 10.3389/fcimb.2022.895022] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 05/02/2022] [Indexed: 12/03/2022] Open
Abstract
The leading cause of treatment failure in Staphylococcus aureus infections is the development of biofilms. Biofilms are highly tolerant to conventional antibiotics which were developed against planktonic cells. Consequently, there is a lack of antibiofilm agents in the antibiotic development pipeline. To address this problem, we developed a platelet-rich plasma (PRP)-derived biologic, termed BIO-PLY (for the BIOactive fraction of Platelet-rich plasma LYsate) which has potent in vitro bactericidal activity against S. aureus synovial fluid free-floating biofilm aggregates. Additional in vitro studies using equine synoviocytes and chondrocytes showed that BIO-PLY protected these cells of the joint from inflammation. The goal of this study was to test BIO-PLY for in vivo efficacy using an equine model of infectious arthritis. We found that horses experimentally infected with S. aureus and subsequently treated with BIO-PLY combined with the antibiotic amikacin (AMK) had decreased bacterial concentrations within both synovial fluid and synovial tissue and exhibited lower systemic and local inflammatory scores compared to horses treated with AMK alone. Most importantly, AMK+BIO-PLY treatment reduced the loss of infection-associated cartilage proteoglycan content in articular cartilage and decreased synovial tissue fibrosis and inflammation. Our results demonstrate the in vivo efficacy of AMK+BIO-PLY and represents a new approach to restore and potentiate antimicrobial activity against synovial fluid biofilms.
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Affiliation(s)
- Jessica M. Gilbertie
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States
| | - Thomas P. Schaer
- Department of Clinical Studies New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Julie B. Engiles
- Department of Clinical Studies New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
- Department of Pathobiology New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Gabriela S. Seiler
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Bennett L. Deddens
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Alicia G. Schubert
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Megan E. Jacob
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Darko Stefanovski
- Department of Clinical Studies New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Gordon Ruthel
- Department of Pathobiology New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States
| | - Noreen J. Hickok
- Department of Orthopedic Surgery, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, United States
| | - Devorah M. Stowe
- Department of Population Health and Pathobiology, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Alexa Frink
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
| | - Lauren V. Schnabel
- Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, United States
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States
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Yan H, Shi J, Dai Y, Li X, Wu Y, Zhang J, Gu Z, Zhang C, Leng J. Technique integration of single-cell RNA sequencing with spatially resolved transcriptomics in the tumor microenvironment. Cancer Cell Int 2022; 22:155. [PMID: 35440049 PMCID: PMC9020011 DOI: 10.1186/s12935-022-02580-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Accepted: 04/08/2022] [Indexed: 12/05/2022] Open
Abstract
Background The tumor microenvironment contributes to tumor initiation, growth, invasion, and metastasis. The tumor microenvironment is heterogeneous in cellular and acellular components, particularly structural features and their gene expression at the inter-and intra-tumor levels. Main text Single-cell RNA sequencing profiles single-cell transcriptomes to reveal cell proportions and trajectories while spatial information is lacking. Spatially resolved transcriptomics redeems this lack with limited coverage or depth of transcripts. Hence, the integration of single-cell RNA sequencing and spatial data makes the best use of their strengths, having insights into exploring diverse tissue architectures and interactions in a complicated network. We review applications of integrating the two methods, especially in cellular components in the tumor microenvironment, showing each role in cancer initiation and progression, which provides clinical relevance in prognosis, optimal treatment, and potential therapeutic targets. Conclusion The integration of two approaches may break the bottlenecks in the spatial resolution of neighboring cell subpopulations in cancer, and help to describe the signaling circuitry about the intercommunication and its exact mechanisms in producing different types and malignant stages of tumors.
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Affiliation(s)
- Hailan Yan
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Jinghua Shi
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Yi Dai
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Xiaoyan Li
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Yushi Wu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Jing Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Zhiyue Gu
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Chenyu Zhang
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China
| | - Jinhua Leng
- Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China. .,National Clinical Research Center for Obstetric & Gynecologic Diseases, No.1 Shuaifuyuan Dongcheng District, Beijing, 100730, China.
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Yang H, Yan M, Li W, Xu L. SIRPα and PD1 expression on tumor-associated macrophage predict prognosis of intrahepatic cholangiocarcinoma. J Transl Med 2022; 20:140. [PMID: 35317832 PMCID: PMC8939174 DOI: 10.1186/s12967-022-03342-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/06/2022] [Indexed: 02/08/2023] Open
Abstract
Background The phagocytosis checkpoints of CD47/SIRPα, PD1/PDL1, CD24/SIGLEC10, and MHC/LILRB1 have shown inhibited phagocytosis of macrophages in distinct tumors. However, phagocytosis checkpoints and their therapeutic significance remain largely unknown in intrahepatic cholangiocarcinoma (ICC) patients. Methods We analyzed sequencing data from the Cancer Genome Atlas (TCGA) and identified differently expressed genes between tumors and para‐tumors. Then, we investigated the expression of CD68, SIRPα, PD1, and SIGLEC10 by IHC in 81 ICC patients, and the clinical significance of these markers with different risk factors was also measured. Results Tumor infiltration immune cells analysis from the TCGA data revealed that macrophages significantly increased. Further analysis showed that M0 macrophages were significantly higher and M2 macrophages were significantly lower in ICC compared with paracancerous tissues, while there was no significant difference in M1 macrophages. We then examined some of M1 and M2 markers, and we found that M1 markers (iNOS, TNF, IL12A, and B) increased, while M2 markers (ARG1 and CD206) decreased in ICCs compared with paracancerous tissues. Furthermore, the expression of CD68, SIRPα, PD1, and SIGLEC10 increased significantly, but LILRB1 expression did not. We also examined the expression of CD68, SIRPα, PD1, and SIGLEC10 in 81 ICC patients by IHC, which revealed a similar expression pattern to that which emerged from the TCGA data. Upon analyzing the correlation between these markers and the progression of ICC patients, we found that the high expression of CD68, SIRPα, and PD1 are correlated with poor progression among ICC patients, while SIGLEC10 shows no correlation. More SIRPα+ or PD1+ TAMs were observed in the tumor tissues of ICC patients with HBV infections compared to non‐HBV‐infected patients. Multivariate analysis indicated that SIRPα and PD1 expression are independent indicators of ICC patient prognosis. Conclusion Hyperactivated CD47/SIRPα and PD1/PD‐L1 signals in CD68+ TAMs in tumor tissues are negative prognostic markers for ICCs after resection. Furthermore, anti-CD47 in combination with anti-PD1 or CD47/PD1 bispecific antibody (BsAb) may represent promising treatments for ICC. Further studies are also required in the future to confirmed our findings.
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Affiliation(s)
- Hui Yang
- Department of Gastroenterology, Zhengzhou University People's Hospital and Henan Provincial People's Hospital, Zhengzhou, 450003, Henan, China
| | - Meimei Yan
- Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China
| | - Wei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China
| | - Linping Xu
- Department of Research and Foreign Affairs, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, 450008, China.
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Qian H, Zhou T, Fu Y, Guo M, Yang W, Zhang D, Fang W, Yao M, Shi H, Chai C, Cheng W, Ding S, Chen T. Self-assembled tetrahedral framework nucleic acid mediates tumor-associated macrophage reprogramming and restores antitumor immunity. MOLECULAR THERAPY. NUCLEIC ACIDS 2022; 27:763-773. [PMID: 35116188 PMCID: PMC8783116 DOI: 10.1016/j.omtn.2021.12.036] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Accepted: 12/31/2021] [Indexed: 12/20/2022]
Abstract
There is increasing interest in depleting or repolarizing tumor-associated macrophages (TAMs) to generate a proinflammatory effect. However, TAMs usually display an immunosuppressive M2-like phenotype in the tumor microenvironment. Apparently, developing a macrophage-targeting delivery system with immunomodulatory agents is urgent. In this study, an efficient siRNA and CpG ODNs delivery system (CpG-siRNA-tFNA) was prepared with nucleic acid stepwise self-assembled. The tFNA composed of CpG ODNs and siRNA showed a higher stability and an enhanced cellular uptake efficiency. Moreover, the CpG-siRNA-tFNA effectively reprogrammed TAMs toward M1 phenotype polarization with increased proinflammatory cytokine secretion and NF-κB signal pathway activation, which triggers dramatic antitumor immune responses. Additionally, the CpG-siRNA-tFNA exhibited superior antitumor efficacy in a breast cancer xenograft mouse model without obvious systemic side effects. Taken together, CpG-siRNA-tFNA displayed greatly antitumor effect by facilitating TAM polarization toward M1 phenotypes in favor of immunotherapy. Hence, we have developed an efficient therapeutic strategy with immunomodulatory agents for clinical applications.
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Affiliation(s)
- Husun Qian
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Ting Zhou
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Yixin Fu
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Minkang Guo
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Wu Yang
- Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Dian Zhang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wenli Fang
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Mengli Yao
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - He Shi
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Chengsen Chai
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Wei Cheng
- The Center for Clinical Molecular Medical Detection, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Shijia Ding
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
| | - Tingmei Chen
- Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), College of Laboratory Medicine, Chongqing Medical University, Chongqing 400016, P.R. China
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Ito M, Nakano M, Ariyama H, Yamaguchi K, Tanaka R, Semba Y, Sugio T, Miyawaki K, Kikushige Y, Mizuno S, Isobe T, Tanoue K, Taguchi R, Ueno S, Kawano T, Murata M, Baba E, Akashi K. Macrophages are primed to transdifferentiate into fibroblasts in malignant ascites and pleural effusions. Cancer Lett 2022; 532:215597. [PMID: 35150810 DOI: 10.1016/j.canlet.2022.215597] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 02/02/2022] [Accepted: 02/08/2022] [Indexed: 11/02/2022]
Abstract
Cancer-associated fibroblasts (CAFs) play an important role in cancer progression. However, the origin of CAFs remains unclear. This study shows that macrophages in malignant ascites and pleural effusions (cavity fluid-associated macrophages: CAMs) transdifferentiate into fibroblast-like cells. CAMs obtained from gastrointestinal cancer patients were sorted by flow cytometry and cultured in vitro. CD45+CD14+ CAMs transdifferentiated into CD45-CD90+ fibroblast-like cells that exhibited spindle shapes. Then, cDNA microarray analysis showed that the CD45-CD90+ fibroblast-like cells (macrophage-derived CAFs: MDCAFs) had a fibroblast-specific gene expression signature and produced growth factors for epithelial cell proliferation. Human colon cancer cells transplanted into immunodeficient mice with MDCAFs formed larger tumors than cancer cells alone. Gene ontology analyses showed the involvement of TGFβ signaling and cell-matrix adhesion in MDCAFs, and transdifferentiation of CAMs into MDCAFs was canceled by inhibiting TGFβ and cell adhesion. Furthermore, the acquired genetic alterations in hematopoietic stem cells (HSCs) were shared in CAMs and MDCAFs. Taken together, CAMs could be a source of CAFs and might originate from HSCs. We propose the transdifferentiation process of CAMs into MDCAFs as a new therapeutic target for fibrosis associated with gastrointestinal cancer.
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Affiliation(s)
- Mamoru Ito
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Michitaka Nakano
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hiroshi Ariyama
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kyoko Yamaguchi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Risa Tanaka
- Department of Medical Oncology, Hamanomachi Hospital, Fukuoka, Japan
| | - Yuichiro Semba
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takeshi Sugio
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kohta Miyawaki
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yoshikane Kikushige
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Shinichi Mizuno
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Taichi Isobe
- Department of Oncology and Social Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenro Tanoue
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Ryosuke Taguchi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Shohei Ueno
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Takahito Kawano
- Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan
| | - Masaharu Murata
- Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan
| | - Eishi Baba
- Department of Oncology and Social Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Koichi Akashi
- Department of Medicine and Biosystemic Science, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
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Yoshida C, Kadota K, Ishikawa R, Go T, Haba R, Yokomise H. OUP accepted manuscript. Interact Cardiovasc Thorac Surg 2022; 34:1081-1088. [PMID: 35079802 PMCID: PMC9159418 DOI: 10.1093/icvts/ivac005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 12/11/2021] [Accepted: 01/12/2022] [Indexed: 11/17/2022] Open
Affiliation(s)
- Chihiro Yoshida
- Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Kyuichi Kadota
- Department of Pathology, Faculty of Medicine, Shimane University, Shimane, Japan
- Corresponding author. Department of Pathology, Faculty of Medicine, Shimane University, 89-1 Enya, Izumo, Shimane 693-8501, Japan. Tel: +81-87-891-2305; fax: +81-87-891-2191; e-mail: (K. Kadota)
| | - Ryo Ishikawa
- Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Tetsuhiko Go
- Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Reiji Haba
- Department of Diagnostic Pathology, Faculty of Medicine, Kagawa University, Kagawa, Japan
| | - Hiroyasu Yokomise
- Department of General Thoracic Surgery, Faculty of Medicine, Kagawa University, Kagawa, Japan
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Jaramillo-Valverde L, Levano KS, Capristano S, Tarazona DD, Cisneros A, Yufra-Picardo VM, Valdivia-Silva J, Guio H. CXCR4 Knockdown Via CRISPR/CAS9 in a Tumor-Associated Macrophage Model Decreases Human Breast Cancer Cell Migration. Cureus 2021; 13:e20842. [PMID: 35111484 PMCID: PMC8794389 DOI: 10.7759/cureus.20842] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/30/2021] [Indexed: 11/25/2022] Open
Abstract
Introduction Breast cancer is the leading cause of cancer-related deaths in women worldwide with the majority of deaths due to metastasis. The development of metastasis is closely related to the tumor microenvironment where tumor-associated macrophages (TAMs) are the main immune cell component playing a crucial role in tumor migration. Key players in tumor progression, metastasis and survival are the receptor CXCR4 and its ligand CXCL12. CXCR4 is expressed in multiple cell types including macrophages and breast cancer cells. Many studies have focus on the role of CXCR4 expressed in breast cancer cells. Methods In this study, we investigated the role of CXCR4 expressed in TAMs on breast cancer cell migration by reducing CXCR4 expression via CRISPR-CAS9 system in differentiated THP-1 cells (a TAMs model). Results According to wound healing migration assay, MCF7 cancer cells co-cultured with genetically edited dTHP-1 cells have a lower migration rate as compared to MCF7 cancer cells co-cultured with unedited and dTHP-1 cells. Conclusion The study demonstrates the role of CXCR4 on breast cancer cell migration through TAM-cancer cell crosstalk.
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Multifaceted Roles of Chemokines and Chemokine Receptors in Tumor Immunity. Cancers (Basel) 2021; 13:cancers13236132. [PMID: 34885241 PMCID: PMC8656932 DOI: 10.3390/cancers13236132] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/26/2021] [Accepted: 12/02/2021] [Indexed: 12/22/2022] Open
Abstract
Simple Summary Various immune cells are involved in host immune responses to cancer. T-helper (Th) 1 cells, cytotoxic CD8+ T cells, and natural killer cells are the major effector cells in anti-tumor immunity, whereas cells such as regulatory T cells and myeloid-derived suppressor cells are negatively involved in anti-tumor immunity. Th2 cells and Th17 cells have been shown to have both pro-tumor and anti-tumor activities. The migratory properties of various immune cells are essential for their function and critically regulated by the chemokine superfamily. In this review, we summarize the roles of various immune cells in tumor immunity and their migratory regulation by the chemokine superfamily. We also assess the therapeutic possibilities of targeting chemokines and chemokine receptors in cancer immunotherapy. Abstract Various immune cells are involved in host tumor immune responses. In particular, there are many T cell subsets with different roles in tumor immunity. T-helper (Th) 1 cells are involved in cellular immunity and thus play the major role in host anti-tumor immunity by inducing and activating cytotoxic T lymphocytes (CTLs). On the other hand, Th2 cells are involved in humoral immunity and suppressive to Th1 responses. Regulatory T (Treg) cells negatively regulate immune responses and contribute to immune evasion of tumor cells. Th17 cells are involved in inflammatory responses and may play a role in tumor progression. However, recent studies have also shown that Th17 cells are capable of directly inducting CTLs and thus may promote anti-tumor immunity. Besides these T cell subsets, there are many other innate immune cells such as dendritic cells (DCs), natural killer (NK) cells, and myeloid-derived suppressor cells (MDSCs) that are involved in host immune responses to cancer. The migratory properties of various immune cells are critical for their functions and largely regulated by the chemokine superfamily. Thus, chemokines and chemokine receptors play vital roles in the orchestration of host immune responses to cancer. In this review, we overview the various immune cells involved in host responses to cancer and their migratory properties regulated by the chemokine superfamily. Understanding the roles of chemokines and chemokine receptors in host immune responses to cancer may provide new therapeutic opportunities for cancer immunotherapy.
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Ye P, Chi X, Cha JH, Luo S, Yang G, Yan X, Yang WH. Potential of E3 Ubiquitin Ligases in Cancer Immunity: Opportunities and Challenges. Cells 2021; 10:cells10123309. [PMID: 34943817 PMCID: PMC8699390 DOI: 10.3390/cells10123309] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/13/2022] Open
Abstract
Cancer immunotherapies, including immune checkpoint inhibitors and immune pathway–targeted therapies, are promising clinical strategies for treating cancer. However, drug resistance and adverse reactions remain the main challenges for immunotherapy management. The future direction of immunotherapy is mainly to reduce side effects and improve the treatment response rate by finding new targets and new methods of combination therapy. Ubiquitination plays a crucial role in regulating the degradation of immune checkpoints and the activation of immune-related pathways. Some drugs that target E3 ubiquitin ligases have exhibited beneficial effects in preclinical and clinical antitumor treatments. In this review, we discuss mechanisms through which E3 ligases regulate tumor immune checkpoints and immune-related pathways as well as the opportunities and challenges for integrating E3 ligases targeting drugs into cancer immunotherapy.
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Affiliation(s)
- Peng Ye
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Xiaoxia Chi
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Jong-Ho Cha
- Department of Biomedical Science and Engineering, Graduate School, Inha University, Incheon 22212, Korea;
- Department of Biomedical Sciences, College of Medicine, Inha University, Incheon 22212, Korea
| | - Shahang Luo
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Guanghui Yang
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
| | - Xiuwen Yan
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
- Correspondence: (X.Y.); (W.-H.Y.)
| | - Wen-Hao Yang
- Key Laboratory of Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes and Affiliated Cancer Hospital & Institute, Guangzhou Medical University, Guangzhou 910095, China; (P.Y.); (X.C.); (S.L.); (G.Y.)
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 406040, Taiwan
- Correspondence: (X.Y.); (W.-H.Y.)
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Hussain K, Cragg MS, Beers SA. Remodeling the Tumor Myeloid Landscape to Enhance Antitumor Antibody Immunotherapies. Cancers (Basel) 2021; 13:4904. [PMID: 34638388 PMCID: PMC8507767 DOI: 10.3390/cancers13194904] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 09/16/2021] [Accepted: 09/26/2021] [Indexed: 12/30/2022] Open
Abstract
Among the diverse tumor resident immune cell types, tumor-associated macrophages (TAMs) are often the most abundant, possess an anti-inflammatory phenotype, orchestrate tumor immune evasion and are frequently associated with poor prognosis. However, TAMs can also be harnessed to destroy antibody-opsonized tumor cells through the process of antibody-dependent cellular phagocytosis (ADCP). Clinically important tumor-targeting monoclonal antibodies (mAb) such as Rituximab, Herceptin and Cetuximab, function, at least in part, by inducing macrophages to eliminate tumor cells via ADCP. For IgG mAb, this is mediated by antibody-binding activating Fc gamma receptors (FcγR), with resultant phagocytic activity impacted by the level of co-engagement with the single inhibitory FcγRIIb. Approaches to enhance ADCP in the tumor microenvironment include the repolarization of TAMs to proinflammatory phenotypes or the direct augmentation of ADCP by targeting so-called 'phagocytosis checkpoints'. Here we review the most promising new strategies targeting the cell surface molecules present on TAMs, which include the inhibition of 'don't eat me signals' or targeting immunostimulatory pathways with agonistic mAb and small molecules to augment tumor-targeting mAb immunotherapies and overcome therapeutic resistance.
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Affiliation(s)
| | | | - Stephen A. Beers
- Centre for Cancer Immunology, School of Cancer Sciences, Faculty of Medicine, University of Southampton, Tremona Road, Southampton SO16 6YD, UK; (K.H.); (M.S.C.)
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