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Salahi‐Niri A, Zarand P, Shojaeian F, Mansouri N, Yazdani O, Esbati R, Safavi‐Naini SAA, Jahanbin B. Proliferative Markers in Breast Cancer and Chemotherapy Implications: A Comprehensive Review. Health Sci Rep 2025; 8:e70626. [PMID: 40201702 PMCID: PMC11976874 DOI: 10.1002/hsr2.70626] [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: 05/07/2024] [Revised: 02/26/2025] [Accepted: 03/09/2025] [Indexed: 04/10/2025] Open
Abstract
Background and Aims Breast cancer is the most common cancer and a leading cause of cancer-related death among women globally. Determining which patients will benefit from chemotherapy remains challenging. Proliferative markers such as Ki-67, mini chromosome maintenance (MCM) proteins, and proliferating cell nuclear antigen (PCNA) offer valuable insights into tumor growth and treatment response. This review evaluates their clinical roles, with a focus on chemotherapy implications and emerging digital pathology techniques for marker quantification. Methods A narrative review was conducted by searching PubMed, Scopus, and Google Scholar for studies related to Ki-67, MCM, PCNA, breast cancer, and chemotherapy. Studies were thematically categorized into five areas. A bibliometric analysis of publications from 2000 to April 2023 was performed using the Bibliometrix R package and VOSviewer to assess research trends and thematic evolution. Results Eighty studies were included in the narrative synthesis. Ki-67 is the most commonly used marker, particularly useful in predicting response to neoadjuvant chemotherapy (NAC). MCM proteins show promise for identifying proliferative potential across tumor grades, while PCNA is associated with aggressive tumor features and poor prognosis. Post-chemotherapy changes in Ki-67 levels are linked to survival outcomes. Bibliometric analysis revealed a shift in research focus from basic mechanisms to clinical applications and digital quantification. Conclusion Proliferative markers play an essential role in breast cancer management. Ki-67 remains a key predictor of chemotherapy response, while MCM and PCNA offer complementary prognostic insights. Integration of these markers with digital pathology and AI-driven tools may enhance diagnostic accuracy and personalized treatment strategies. Standardization of assessment methods is crucial for broader clinical application.
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Affiliation(s)
- Aryan Salahi‐Niri
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Paniz Zarand
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Fatemeh Shojaeian
- Sidney Kimmel Comprehensive Cancer Research CenterJohns Hopkins School of MedicineBaltimoreMarylandUSA
| | - Negar Mansouri
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Omid Yazdani
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Romina Esbati
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
| | - Seyed Amir Ahmad Safavi‐Naini
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research, Institute for Gastroenterology and Liver DiseasesShahid Beheshti University of Medical SciencesTehranIran
- Division of Data‐Driven and Digital Medicine (D3M)Icahn School of Medicine at Mount SinaiNew YorkUSA
| | - Behnaz Jahanbin
- Cancer Institute, Pathology Department, Imam Khomeini Hospital ComplexTehran University of Medical SciencesTehranIran
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Theodorou SDP, Ntostoglou K, Nikas IP, Goutas D, Georgoulias V, Kittas C, Pateras IS. Double-Multiplex Immunostainings for Immune Profiling of Invasive Breast Carcinoma: Emerging Novel Immune-Based Biomarkers. Int J Mol Sci 2025; 26:2838. [PMID: 40243442 PMCID: PMC11988469 DOI: 10.3390/ijms26072838] [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: 01/24/2025] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 04/18/2025] Open
Abstract
The role of tumor microenvironment in invasive breast cancer prognosis and treatment is highly appreciated. With the advent of immunotherapy, immunophenotypic characterization in primary tumors is gaining attention as it can improve patient stratification. Here, we discuss the benefits of spatial analysis employing double and multiplex immunostaining, allowing the simultaneous detection of more than one protein on the same tissue section, which in turn helps us provide functional insight into infiltrating immune cells within tumors. We focus on studies demonstrating the prognostic and predictive impact of distinct tumor-infiltrating lymphocyte subpopulations including different CD8(+) T subsets as well as CD4(+) T cells and tumor-associated macrophages in invasive breast carcinoma. The clinical value of immune cell topography is also appreciated. We further refer to how the integration of digital pathology and artificial intelligence in routine practice could enhance the accuracy of multiplex immunostainings evaluation within the tumor microenvironment, maximizing our perception of host immune response, improving in turn decision-making towards more precise immune-associated therapies.
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Affiliation(s)
- Sofia D. P. Theodorou
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.D.P.T.); (K.N.); (C.K.)
| | - Konstantinos Ntostoglou
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.D.P.T.); (K.N.); (C.K.)
| | - Ilias P. Nikas
- Medical School, University of Cyprus, 2029 Nicosia, Cyprus;
| | - Dimitrios Goutas
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | | | - Christos Kittas
- Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (S.D.P.T.); (K.N.); (C.K.)
| | - Ioannis S. Pateras
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 12462 Athens, Greece;
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Chaudhary A, Patil P, Raina P, Kaul-Ghanekar R. Matairesinol repolarizes M2 macrophages to M1 phenotype to induce apoptosis in triple-negative breast cancer cells. Immunopharmacol Immunotoxicol 2024:1-15. [PMID: 39722605 DOI: 10.1080/08923973.2024.2425028] [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: 06/05/2024] [Accepted: 10/27/2024] [Indexed: 12/28/2024]
Abstract
OBJECTIVE Triple-Negative Breast Cancer (TNBC), the most challenging subtype of Breast Cancer (BC), currently lacks targeted therapy, presenting a significant therapeutic gap in its management. Tumor Associated Macrophages (TAMs) play a significant role in TNBC progression and could be targeted by repolarizing them from M2 to M1 phenotype. Matairesinol (MAT), a plant lignan, has been shown to exhibit anticancer, anti-inflammatory and immunomodulatory activities. In this study, we explored how MAT-induced repolarization of THP-1-derived M2 macrophages towards the M1 phenotype, which could effectively target the TNBC cell line, MDA-MB-231. METHODS The differential expression of genes in THP-1-derived macrophages at mRNA levels was evaluated by RNAseq assay. An inverted microscope equipped with a CMOS camera was utilized to capture the morphological variations in THP-1 cells and THP-1-derived macrophages. Relative mRNA expression of M1 and M2 specific marker genes was quantified by qRT-PCR. Cell viability and induction of apoptosis were evaluated by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide (JC-1 dye) assays, respectively. RESULTS MAT reduced the viability of M2a and M2d macrophages and repolarized them to M1 phenotype. Conditioned medium (CM) from MAT-treated M2a and M2d macrophages significantly reduced the viability of TNBC cells by apoptosis. CONCLUSION Targeting M2 macrophages is an important strategy to regulate cancer progression. Our study provides evidence that MAT may be a promising drug candidate for developing novel anti-TNBC therapy. However, further studies are warranted to thoroughly elucidate the molecular mechanism of action of MAT and evaluate its therapeutic potential in TNBC in vitro and in vivo models.
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Affiliation(s)
- Amol Chaudhary
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Prajakta Patil
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
| | - Prerna Raina
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
- Analytical Department (ADT), Lupin Limited, Pune, India
| | - Ruchika Kaul-Ghanekar
- Cancer Research Lab, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be University), Pune, India
- Symbiosis Centre for Research and Innovation (SCRI); Symbiosis International Deemed University (SIU), Pune, India
- Cancer Research Lab, Symbiosis School of Biological Sciences (SSBS), Symbiosis International Deemed University (SIU), Pune, India
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He X, Ran Q, Li X, Xiong A, Zhang L, Jiang M, Bai L, Peng D, Wang J, Sun B, Li G. Candida albicans-Derived β-Glucan as a Novel Modulator of Tumor Microenvironment: Targeting Macrophage Polarization and Inducing Ferroptosis in Lung Cancer. J Inflamm Res 2024; 17:10479-10494. [PMID: 39659749 PMCID: PMC11630740 DOI: 10.2147/jir.s489191] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Accepted: 11/23/2024] [Indexed: 12/12/2024] Open
Abstract
Introduction Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and their polarization state significantly influences patient outcomes. This study investigates the inhibitory effects of β-glucan extracted from Candida albicans on lung cancer progression, focusing on its impact on TAM polarization and the induction of ferroptosis, a form of regulated cell death. Methods Utilizing both in vivo animal models and in vitro cellular assays, we assessed the impact of β-glucan on tumor growth, cellular proliferation, and migration. We evaluated TAM polarization by analyzing the expression of M1 and M2 markers and identified differentially expressed genes (DEGs) related to ferroptosis. The role of ferroptosis in TAM polarization was further confirmed by assessing the protein levels of ACSL4 and GPX4, intracellular ferrous ion levels, and lipid peroxides. Results β-glucan treatment significantly reduced tumor size and weight, along with cellular proliferation and migration, suggesting a potent suppressive effect on lung cancer cell growth. β-glucan promoted an M1-like phenotype in TAMs, as evidenced by increased CD86 expression and decreased CD206 expression, and modulated cytokine mRNA levels. RNA sequencing analysis post β-glucan treatment identified a substantial number of DEGs enriched in the ferroptosis pathway. The induction of ferroptosis by β-glucan was further confirmed through the significant upregulation of ACSL4 and downregulation of GPX4, alongside increased intracellular ferrous ion levels and lipid peroxides. The ferroptosis inhibitor Fer-1 abrogated these effects, highlighting the specificity of β-glucan-mediated polarization. Conclusion These results collectively provide novel insights into the immunotherapeutic potential of β-glucan from Candida albicans and its role in modulating TAM polarization and lung cancer growth, offering a promising avenue for cancer treatment strategies.
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Affiliation(s)
- Xiang He
- National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
| | - Qin Ran
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
| | - Xiaolan Li
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
| | - Anying Xiong
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
| | - Lei Zhang
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
| | - Manling Jiang
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
| | - Lingling Bai
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
| | - Dan Peng
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
| | - Junyi Wang
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
| | - Baoqing Sun
- National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China
| | - Guoping Li
- National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510120, People’s Republic of China
- Laboratory of Allergy and Precision Medicine, Chengdu Institute of Respiratory Health, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, 610031, People’s Republic of China
- Department of Respiration, Chengdu third People’s hospital Branch of National Clinical Research Center for Respiratory Disease, Affiliated Hospital of ChongQing Medical University, Chengdu, 610031, People’s Republic of China
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Park SM, Chen CJJ, Verdon DJ, Ooi MPY, Brooks AES, Martin RCW, Mathy JA, Emanuel PO, Dunbar PR. Proliferating macrophages in human tumours show characteristics of monocytes responding to myelopoietic growth factors. Front Immunol 2024; 15:1412076. [PMID: 38903497 PMCID: PMC11188303 DOI: 10.3389/fimmu.2024.1412076] [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: 04/04/2024] [Accepted: 05/16/2024] [Indexed: 06/22/2024] Open
Abstract
Macrophages play essential roles in maintaining tissue homeostasis and immune defence. However, their extensive infiltration into tumours has been linked to adverse outcomes in multiple human cancers. Within the tumour microenvironment (TME), tumour-associated macrophages (TAMs) promote tumour growth and metastasis, making them prime targets for cancer immunotherapy. Recent single-cell analysis suggest that proliferating TAMs accumulate in human cancers, yet their origins and differentiation pathways remain uncertain. Here, we show that a subpopulation of CD163+ TAMs proliferates in situ within the TME of melanoma, lung cancer, and breast cancer. Consistent with their potential role in suppressing anti-tumour activities of T cells, CD163+ TAMs express a range of potent immunosuppressive molecules, including PD-L1, PD-L2, IL-10, and TGF-β. Other phenotypic markers strongly suggested that these cells originate from CD14+ CCR2+ monocytes, a cell population believed to have minimal capacity for proliferation. However, we demonstrate in vitro that certain myelopoietic cytokines commonly available within the TME induce robust proliferation of human monocytes, especially the combination of interleukin 3 (IL-3) and Macrophage Colony-Stimulating Factor 1 (M-CSF). Monocytic cells cultured with these cytokines efficiently modulate T cell proliferation, and their molecular phenotype recapitulates that of CD163+ TAMs. IL-3-driven proliferation of monocytic cells can be completely blocked by IL-4, associated with the induction of CDKN1A, alongside the upregulation of transcription factors linked to dendritic cell function, such as BATF3 and IRF4. Taken together, our work suggests several novel therapeutic routes to reducing immunosuppressive TAMs in human tumours, from blocking chemokine-mediated recruitment of monocytes to blocking their proliferation.
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Affiliation(s)
- Saem Mul Park
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre, Auckland, New Zealand
| | - Chun-Jen J. Chen
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre, Auckland, New Zealand
| | - Daniel J. Verdon
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre, Auckland, New Zealand
| | - Marcus P. Y. Ooi
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
| | - Anna E. S. Brooks
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre, Auckland, New Zealand
| | | | - Jon A. Mathy
- Department of Surgery, Faculty of Medical Health Sciences, The University of Auckland, Auckland, New Zealand
- Auckland Regional Plastic, Reconstructive and Hand Surgery Unit, Auckland, New Zealand
| | - Patrick O. Emanuel
- Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - P. Rod Dunbar
- School of Biological Sciences, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre, Auckland, New Zealand
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Fang M, Yin W, Qiu C, Song T, Lin B, Wang Y, Xiong H, Wu S. Stromal B Lymphocytes Affecting Prognosis in Triple-Negative Breast Cancer by Opal/TSA Multiplexed Immunofluorescence. Int J Womens Health 2024; 16:755-767. [PMID: 38706691 PMCID: PMC11067943 DOI: 10.2147/ijwh.s444202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Accepted: 12/28/2023] [Indexed: 05/07/2024] Open
Abstract
Objective Immune cells play a key role in tumor microenvironment. The purpose of this study was to investigate the infiltration and clinical indication of immune cells including their combined prognostic value in microenvironment of triple negative breast cancer. Methods We investigated 100 patients with triple negative breast cancer by Opal/Tyramide Signal Amplification multispectral immunofluorescence between 2003 and 2017 at Zhejiang Provincial people's Hospital. Intratumoral and stromal immune cells of triple negative breast cancer were classified and quantitatively analyzed. Survival outcomes were compared using the Kaplan-Meier method and further analyzed with multivariate analysis. Results Infiltration level of stromal B lymphocytes, stromal and intratumoral CD8+ T cells, stromal CD4+ T cells, stromal PD-L1 and intratumoral tumor associated macrophages 2 cells were shown as independent factors affecting disease-free survival and overall survival in univariate analysis. Stromal B lymphocytes, T stage, N stage and pathological type were independent predictive factors for both DFS and OS in multivariate analysis. We firstly found that patients with B lymphocytes-enriched subtypes have a better prognosis than those with T lymphocytes-enriched subtypes and tumor-associated macrophage-enriched subtypes. Conclusion The present study identified a bunch of immune targets and subtypes, which could be exploited in future combined immunotherapy/chemotherapy strategies for triple negative breast cancer patients.
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Affiliation(s)
- Min Fang
- Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, People’s Republic of China
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Wei Yin
- Department of Radiation Oncology, Hangzhou Cancer Hospital, Hangzhou, Zhejiang, People’s Republic of China
| | - Chunyan Qiu
- National Cancer Center/National Clinical Research Center for Cancer/ Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, People’s Republic of China
| | - Tao Song
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Baihua Lin
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Ying Wang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Hanchu Xiong
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People’s Hospital(Affiliated People’s Hospital), Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China
| | - Shixiu Wu
- Department of Radiation Oncology, The Affiliated Hangzhou Hospital of Nanjing Medical University, Hangzhou, Zhejiang, People’s Republic of China
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Mazan A, Marusiak AA. Protocols for Co-Culture Phenotypic Assays with Breast Cancer Cells and THP-1-Derived Macrophages. J Mammary Gland Biol Neoplasia 2024; 29:4. [PMID: 38340231 PMCID: PMC10858929 DOI: 10.1007/s10911-024-09556-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Tumor mass comprises not only cancer cells but also heterogeneous populations of immune and stromal cells, along with the components of the extracellular matrix, collectively called the tumor microenvironment (TME). This diverse population of cells can communicate with each other, which can positively or negatively affect tumor growth and progression to malignancy. The most common type of immune cells in the TME are macrophages. Macrophages continuously differentiate into a broad landscape of tumor-associated macrophages (TAMs) in response to numerous signals from the TME, which makes studies on TAMs quite challenging. Therefore, implementing reliable protocols is a milestone for drawing consistent conclusions about the interactions between cancer cells and TAMs. Here, we provide the details for the polarization of a human leukemia monocytic cell line, THP-1, into M0, M1 and M2 macrophages. We also present a step-by-step protocol for a transwell co-culture using a human breast cancer cell line, HCC1806, and THP-1-derived macrophages. Finally, we describe the colony formation and migration assays performed on the breast cancer cells after the co-culture with macrophages to measure the influence of macrophages on the oncogenic features of cancer cells. In summary, our co-culture-based protocols can be a valuable resource for investigating the interactions between macrophages and cancer cells.
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Affiliation(s)
- Alicja Mazan
- Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Flisa 6, Warsaw, 02-247, Poland
| | - Anna A Marusiak
- Laboratory of Molecular OncoSignalling, IMol Polish Academy of Sciences, Flisa 6, Warsaw, 02-247, Poland.
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Elfstrum AK, Bapat AS, Schwertfeger KL. Defining and targeting macrophage heterogeneity in the mammary gland and breast cancer. Cancer Med 2024; 13:e7053. [PMID: 38426622 PMCID: PMC10905685 DOI: 10.1002/cam4.7053] [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: 11/08/2023] [Revised: 02/09/2024] [Accepted: 02/16/2024] [Indexed: 03/02/2024] Open
Abstract
INTRODUCTION Macrophages are innate immune cells that are associated with extensive phenotypic and functional plasticity and contribute to normal development, tissue homeostasis, and diseases such as cancer. In this review, we discuss the heterogeneity of tissue resident macrophages in the normal mammary gland and tumor-associated macrophages in breast cancer. Tissue resident macrophages are required for mammary gland development, where they have been implicated in promoting extracellular matrix remodeling, apoptotic clearance, and cellular crosstalk. In the context of cancer, tumor-associated macrophages are key drivers of growth and metastasis via their ability to promote matrix remodeling, angiogenesis, lymphangiogenesis, and immunosuppression. METHOD We identified and summarized studies in Pubmed that describe the phenotypic and functional heterogeneity of macrophages and the implications of targeting individual subsets, specifically in the context of mammary gland development and breast cancer. We also identified and summarized recent studies using single-cell RNA sequencing to identify and describe macrophage subsets in human breast cancer samples. RESULTS Advances in single-cell RNA sequencing technologies have yielded nuances in macrophage heterogeneity, with numerous macrophage subsets identified in both the normal mammary gland and breast cancer tissue. Macrophage subsets contribute to mammary gland development and breast cancer progression in differing ways, and emerging studies highlight a role for spatial localization in modulating their phenotype and function. CONCLUSION Understanding macrophage heterogeneity and the unique functions of each subset in both normal mammary gland development and breast cancer progression may lead to more promising targets for the treatment of breast cancer.
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Affiliation(s)
- Alexis K. Elfstrum
- Microbiology, Immunology, and Cancer Biology Graduate ProgramUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Aditi S. Bapat
- Molecular Pharmacology and Therapeutics Graduate ProgramUniversity of MinnesotaMinneapolisMinnesotaUSA
| | - Kathryn L. Schwertfeger
- Department of Laboratory Medicine and PathologyUniversity of MinnesotaMinneapolisMinnesotaUSA
- Masonic Cancer CenterUniversity of MinnesotaMinneapolisMinnesotaUSA
- Center for ImmunologyUniversity of MinnesotaMinneapolisMinnesotaUSA
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Domínguez-Cejudo MA, Gil-Torralvo A, Cejuela M, Molina-Pinelo S, Salvador Bofill J. Targeting the Tumor Microenvironment in Breast Cancer: Prognostic and Predictive Significance and Therapeutic Opportunities. Int J Mol Sci 2023; 24:16771. [PMID: 38069096 PMCID: PMC10706312 DOI: 10.3390/ijms242316771] [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: 10/25/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
Breast cancer is one of the most prevalent tumors among women. Its prognosis and treatment outcomes depend on factors related to tumor cell biology. However, recent studies have revealed the critical role of the tumor microenvironment (TME) in the development, progression, and treatment response of breast cancer. In this review, we explore the different components of the TME and their relevance as prognostic and predictive biomarkers in breast cancer. In addition, techniques for assessing the tumor microenvironment, such as immunohistochemistry or gene expression profiling, and their clinical utility in therapeutic decision-making are examined. Finally, therapeutic strategies targeting the TME are reviewed, highlighting their potential clinical benefits. Overall, this review emphasizes the importance of the TME in breast cancer and its potential as a clinical tool for better patient stratification and the design of personalized therapies.
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Affiliation(s)
- María A. Domínguez-Cejudo
- Institute of Biomedicine of Seville (IBiS), HUVR, CSIC, Universidad de Sevilla, 41013 Seville, Spain (S.M.-P.)
- Andalusian—Roche Network Mixed Alliance in Precision Medical Oncology, 41092 Sevilla, Spain
| | - Ana Gil-Torralvo
- Institute of Biomedicine of Seville (IBiS), HUVR, CSIC, Universidad de Sevilla, 41013 Seville, Spain (S.M.-P.)
- Andalusian—Roche Network Mixed Alliance in Precision Medical Oncology, 41092 Sevilla, Spain
- Medical Oncology Department, Virgen del Rocio Hospital, 41013 Seville, Spain
| | - Mónica Cejuela
- Medical Oncology Department, Virgen del Rocio Hospital, 41013 Seville, Spain
| | - Sonia Molina-Pinelo
- Institute of Biomedicine of Seville (IBiS), HUVR, CSIC, Universidad de Sevilla, 41013 Seville, Spain (S.M.-P.)
- Andalusian—Roche Network Mixed Alliance in Precision Medical Oncology, 41092 Sevilla, Spain
| | - Javier Salvador Bofill
- Institute of Biomedicine of Seville (IBiS), HUVR, CSIC, Universidad de Sevilla, 41013 Seville, Spain (S.M.-P.)
- Andalusian—Roche Network Mixed Alliance in Precision Medical Oncology, 41092 Sevilla, Spain
- Medical Oncology Department, Virgen del Rocio Hospital, 41013 Seville, Spain
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10
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Ben-Chetrit N, Niu X, Sotelo J, Swett AD, Rajasekhar VK, Jiao MS, Stewart CM, Bhardwaj P, Kottapalli S, Ganesan S, Loyher PL, Potenski C, Hannuna A, Brown KA, Iyengar NM, Giri DD, Lowe SW, Healey JH, Geissmann F, Sagi I, Joyce JA, Landau DA. Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.10.24.563749. [PMID: 37961223 PMCID: PMC10634790 DOI: 10.1101/2023.10.24.563749] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2023]
Abstract
Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.
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Affiliation(s)
- Nir Ben-Chetrit
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
- These authors contributed equally
| | - Xiang Niu
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
- These authors contributed equally
- Present address: Genentech, Inc., South San Francisco, CA, USA
| | - Jesus Sotelo
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
| | - Ariel D. Swett
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
| | - Vinagolu K. Rajasekhar
- Orthopedic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria S. Jiao
- Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Caitlin M. Stewart
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
| | - Priya Bhardwaj
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Sanjay Kottapalli
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
| | - Saravanan Ganesan
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
| | - Pierre-Louis Loyher
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Catherine Potenski
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
| | - Assaf Hannuna
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Kristy A. Brown
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Neil M. Iyengar
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Dilip D. Giri
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Scott W. Lowe
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
| | - John H. Healey
- Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Frederic Geissmann
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Irit Sagi
- Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel
| | - Johanna A. Joyce
- Department of Oncology and Ludwig Institute for Cancer Research, University of Lausanne, Switzerland
| | - Dan A. Landau
- Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA
- New York Genome Center, New York, NY, USA
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11
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Baritaki S, Zaravinos A. Cross-Talks between RKIP and YY1 through a Multilevel Bioinformatics Pan-Cancer Analysis. Cancers (Basel) 2023; 15:4932. [PMID: 37894300 PMCID: PMC10605344 DOI: 10.3390/cancers15204932] [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: 09/02/2023] [Revised: 09/28/2023] [Accepted: 10/06/2023] [Indexed: 10/29/2023] Open
Abstract
Recent studies suggest that PEBP1 (also known as RKIP) and YY1, despite having distinct molecular functions, may interact and mutually influence each other's activity. They exhibit reciprocal control over each other's expression through regulatory loops, prompting the hypothesis that their interplay could be pivotal in cancer advancement and resistance to drugs. To delve into this interplay's functional characteristics, we conducted a comprehensive analysis using bioinformatics tools across a range of cancers. Our results confirm the association between elevated YY1 mRNA levels and varying survival outcomes in diverse tumors. Furthermore, we observed differing degrees of inhibitory or activating effects of these two genes in apoptosis, cell cycle, DNA damage, and other cancer pathways, along with correlations between their mRNA expression and immune infiltration. Additionally, YY1/PEBP1 expression and methylation displayed connections with genomic alterations across different cancer types. Notably, we uncovered links between the two genes and different indicators of immunosuppression, such as immune checkpoint blockade response and T-cell dysfunction/exclusion levels, across different patient groups. Overall, our findings underscore the significant role of the interplay between YY1 and PEBP1 in cancer progression, influencing genomic changes, tumor immunity, or the tumor microenvironment. Additionally, these two gene products appear to impact the sensitivity of anticancer drugs, opening new avenues for cancer therapy.
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Affiliation(s)
- Stavroula Baritaki
- Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece;
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, 2404 Nicosia, Cyprus
- Cancer Genetics, Genomics and Systems Biology Group, Basic and Translational Cancer Research Center (BTCRC), 1516 Nicosia, Cyprus
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12
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Li T, Chen Z, Wang Z, Lu J, Chen D. Combined signature of N7-methylguanosine regulators with their related genes and the tumor microenvironment: a prognostic and therapeutic biomarker for breast cancer. Front Immunol 2023; 14:1260195. [PMID: 37868988 PMCID: PMC10585266 DOI: 10.3389/fimmu.2023.1260195] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Accepted: 09/19/2023] [Indexed: 10/24/2023] Open
Abstract
Background Identifying predictive markers for breast cancer (BC) prognosis and immunotherapeutic responses remains challenging. Recent findings indicate that N7-methylguanosine (m7G) modification and the tumor microenvironment (TME) are critical for BC tumorigenesis and metastasis, suggesting that integrating m7G modifications and TME cell characteristics could improve the predictive accuracy for prognosis and immunotherapeutic responses. Methods We utilized bulk RNA-sequencing data from The Cancer Genome Atlas Breast Cancer Cohort and the GSE42568 and GSE146558 datasets to identify BC-specific m7G-modification regulators and associated genes. We used multiple m7G databases and RNA interference to validate the relationships between BC-specific m7G-modification regulators (METTL1 and WDR4) and related genes. Single-cell RNA-sequencing data from GSE176078 confirmed the association between m7G modifications and TME cells. We constructed an m7G-TME classifier, validated the results using an independent BC cohort (GSE20685; n = 327), investigated the clinical significance of BC-specific m7G-modifying regulators by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis, and performed tissue-microarray assays on 192 BC samples. Results Immunohistochemistry and RT-qPCR results indicated that METTL1 and WDR4 overexpression in BC correlated with poor patient prognosis. Moreover, single-cell analysis revealed relationships between m7G modification and TME cells, indicating their potential as indicators of BC prognosis and treatment responses. The m7G-TME classifier enabled patient subgrouping and revealed significantly better survival and treatment responses in the m7Glow+TMEhigh group. Significant differences in tumor biological functions and immunophenotypes occurred among the different subgroups. Conclusions The m7G-TME classifier offers a promising tool for predicting prognosis and immunotherapeutic responses in BC, which could support personalized therapeutic strategies.
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Affiliation(s)
- Tingjun Li
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
- Department of Breast Surgery, Quanzhou First Hospital of Fujian Medical University, Quanzhou, China
| | - Zhishan Chen
- Department of Breast and Thyroid Surgery, Nan’an Hospital, Quanzhou, China
| | - Zhitang Wang
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
- Department of Breast Surgery, Quanzhou First Hospital of Fujian Medical University, Quanzhou, China
| | - Jingyu Lu
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
- Department of Breast Surgery, The Affiliated Hospital of Putian University, Putian, China
| | - Debo Chen
- The School of Clinical Medicine, Fujian Medical University, Fuzhou, China
- Department of Breast Surgery, Quanzhou First Hospital of Fujian Medical University, Quanzhou, China
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13
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Khan SU, Khan MU, Azhar Ud Din M, Khan IM, Khan MI, Bungau S, Hassan SSU. Reprogramming tumor-associated macrophages as a unique approach to target tumor immunotherapy. Front Immunol 2023; 14:1166487. [PMID: 37138860 PMCID: PMC10149956 DOI: 10.3389/fimmu.2023.1166487] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 04/04/2023] [Indexed: 05/05/2023] Open
Abstract
In the last ten years, it has become increasingly clear that tumor-infiltrating myeloid cells drive not just carcinogenesis via cancer-related inflammatory processes, but also tumor development, invasion, and metastasis. Tumor-associated macrophages (TAMs) in particular are the most common kind of leucocyte in many malignancies and play a crucial role in establishing a favorable microenvironment for tumor cells. Tumor-associated macrophage (TAM) is vital as the primary immune cell subset in the tumor microenvironment (TME).In order to proliferate and spread to new locations, tumors need to be able to hide from the immune system by creating an immune-suppressive environment. Because of the existence of pro-tumoral TAMs, conventional therapies like chemotherapy and radiotherapy often fail to restrain cancer growth. These cells are also to blame for the failure of innovative immunotherapies premised on immune-checkpoint suppression. Understanding the series of metabolic changes and functional plasticity experienced by TAMs in the complex TME will help to use TAMs as a target for tumor immunotherapy and develop more effective tumor treatment strategies. This review summarizes the latest research on the TAMs functional status, metabolic changes and focuses on the targeted therapy in solid tumors.
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Affiliation(s)
- Safir Ullah Khan
- Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Munir Ullah Khan
- MOE Key Laboratory of Macromolecular Synthesis and Functionalization, International Research Center for X Polymers, Department of Polymer Science and Engineering, Zhejiang University, Hangzhou, China
| | - Muhammad Azhar Ud Din
- Faculty of Pharmacy, Gomal University Dera Ismail Khan KPK, Dera Ismail Khan, Pakistan
| | - Ibrar Muhammad Khan
- Anhui Province Key Laboratory of Environmental Hormone and Reproduction, School of Biological and Food Engineering Fuyang Normal University, Fuyang, China
| | - Muhammad Imran Khan
- School of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
| | - Syed Shams ul Hassan
- Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
- Department of Natural Product Chemistry, School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China
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14
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Allison E, Edirimanne S, Matthews J, Fuller SJ. Breast Cancer Survival Outcomes and Tumor-Associated Macrophage Markers: A Systematic Review and Meta-Analysis. Oncol Ther 2023; 11:27-48. [PMID: 36484945 PMCID: PMC9935786 DOI: 10.1007/s40487-022-00214-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/14/2022] [Indexed: 12/14/2022] Open
Abstract
INTRODUCTION Tumor-associated macrophages (TAMs) in breast cancer are associated with a poor prognosis. Early studies of TAMs were largely limited to the pan-macrophage marker CD68, however, more recently, an increasing number of studies have used CD163, a marker expressed by alternatively activated M2 macrophages and TAM subsets. We hypothesized that CD163-positive (CD163+) TAMs would be a better predictor of survival outcomes in breast cancer compared to CD68+ TAMs. METHODS We performed a systematic literature search of trials (from 1900 to August 2020) reporting overall survival (OS) or progression-free survival (PFS), breast cancer-specific survival (BCSS), TAM phenotype, and density. Thirty-two studies with 8446 patients were included. Meta-analyses were carried out on hazard ratios (HRs) for survival outcomes of breast cancer patients with a high density of TAMs (CD68+ and/or CD163+) compared to a low density of TAMs. RESULTS A high density of TAMs (CD68+ and/or CD163+) was associated with decreased OS (HR 1.69, 95% CI 1.37-2.07) and reduced PFS (HR 1.64; 95% CI 1.35-1.99). Subgrouping by CD marker type showed a lower OS for high density of CD163+ TAMs (HR 2.24; 95% CI 1.71-2.92) compared to a high density of CD68+ TAMs (HR 1.5; 95% CI 1.12-2). A high density of TAMs (CD68+ and/or CD163+) in triple-negative breast cancer (TNBC) cases was associated with lower OS (HR 2.81, 95% CI 1.35-5.84). CONCLUSION Compared to CD68+ TAMs, a high density of CD163+ TAMs that express a similar phenotype to M2 macrophages are a better predictor of poor survival outcomes in breast cancer.
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Affiliation(s)
- Eleanor Allison
- Sydney Medical School, Nepean Clinical School, The University of Sydney, Level 3, 62 Derby St, Kingswood, NSW, 2747, Australia
| | - Senarath Edirimanne
- Sydney Medical School, Nepean Clinical School, The University of Sydney, Level 3, 62 Derby St, Kingswood, NSW, 2747, Australia
| | - Jim Matthews
- Sydney Informatics Hub, The University of Sydney, Camperdown, NSW, 2006, Australia
| | - Stephen J Fuller
- Sydney Medical School, Nepean Clinical School, The University of Sydney, Level 3, 62 Derby St, Kingswood, NSW, 2747, Australia.
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15
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Peyton SR, Platt MO, Cukierman E. Challenges and Opportunities Modeling the Dynamic Tumor Matrisome. BME FRONTIERS 2023; 4:0006. [PMID: 37849664 PMCID: PMC10521682 DOI: 10.34133/bmef.0006] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Accepted: 11/28/2022] [Indexed: 10/19/2023] Open
Abstract
We need novel strategies to target the complexity of cancer and, particularly, of metastatic disease. As an example of this complexity, certain tissues are particularly hospitable environments for metastases, whereas others do not contain fertile microenvironments to support cancer cell growth. Continuing evidence that the extracellular matrix (ECM) of tissues is one of a host of factors necessary to support cancer cell growth at both primary and secondary tissue sites is emerging. Research on cancer metastasis has largely been focused on the molecular adaptations of tumor cells in various cytokine and growth factor environments on 2-dimensional tissue culture polystyrene plates. Intravital imaging, conversely, has transformed our ability to watch, in real time, tumor cell invasion, intravasation, extravasation, and growth. Because the interstitial ECM that supports all cells in the tumor microenvironment changes over time scales outside the possible window of typical intravital imaging, bioengineers are continuously developing both simple and sophisticated in vitro controlled environments to study tumor (and other) cell interactions with this matrix. In this perspective, we focus on the cellular unit responsible for upholding the pathologic homeostasis of tumor-bearing organs, cancer-associated fibroblasts (CAFs), and their self-generated ECM. The latter, together with tumoral and other cell secreted factors, constitute the "tumor matrisome". We share the challenges and opportunities for modeling this dynamic CAF/ECM unit, the tools and techniques available, and how the tumor matrisome is remodeled (e.g., via ECM proteases). We posit that increasing information on tumor matrisome dynamics may lead the field to alternative strategies for personalized medicine outside genomics.
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Affiliation(s)
- Shelly R. Peyton
- Department of Chemical Engineering, University of Massachusetts Amherst, Amherst, MA, USA
| | - Manu O. Platt
- Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, USA
| | - Edna Cukierman
- Cancer Signaling & Microenvironment Program, Marvin and Concetta Greenberg Pancreatic Cancer Institute, Fox Chase Cancer Center, Temple Health, Philadelphia, PA, USA
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16
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Shapiro GI, Barry SM. Combining PARP Inhibition and Immunotherapy in BRCA-Associated Cancers. Cancer Treat Res 2023; 186:207-221. [PMID: 37978138 DOI: 10.1007/978-3-031-30065-3_12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2023]
Abstract
Poly (ADP-ribose) polymerase (PARP) inhibitors have significantly improved treatment outcomes of homologous recombination (HR) repair-deficient cancers. While the activity of these agents is largely linked to multiple mechanisms underlying the synthetic lethality of PARP inhibition and HR deficiency, emerging data suggest that their efficacy is also tied to their effects on the immune microenvironment and dependent upon cytotoxic T-cell activation. Effects observed in preclinical models are currently being validated in on-treatment biopsy samples procured from patients enrolled in clinical trials. Although this work has stimulated the development of combinations of PARP inhibitors with immunomodulatory agents, results to date have not demonstrated the superiority of combined PARP inhibition and immune checkpoint blockade compared with PARP inhibition alone. These results have stimulated a more comprehensive assessment of the immunosuppressive components of the tumor microenvironment that must be addressed so that the efficacy of PARP inhibitor agents can be maximized.
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Affiliation(s)
- Geoffrey I Shapiro
- Department of Medical Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA.
| | - Suzanne M Barry
- Department of Medical Oncology and Center for DNA Damage and Repair, Dana-Farber Cancer Institute and Harvard Medical School, Boston, USA
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17
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Ghosal S, Hadrava Vanova K, Uher O, Das S, Patel M, Meuter L, Huynh TT, Jha A, Talvacchio S, Knue M, Prodanov T, Zeiger MA, Nilubol N, Taieb D, Crona J, Shankavaram UT, Pacak K. Immune signature of pheochromocytoma and paraganglioma in context of neuroendocrine neoplasms associated with prognosis. Endocrine 2023; 79:171-179. [PMID: 36370152 PMCID: PMC10683554 DOI: 10.1007/s12020-022-03218-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/30/2022] [Indexed: 11/13/2022]
Abstract
PURPOSE To understand prognostic immune cell infiltration signatures in neuroendocrine neoplasms (NENs), particularly pheochromocytoma and paraganglioma (PCPG), we analyzed tumor transcriptomic data from The Cancer Genome Atlas (TCGA) and other published tumor transcriptomic data of NENs. METHODS We used CIBERSORT to infer immune cell infiltrations from bulk tumor transcriptomic data from PCPGs, in comparison to gastroenteropancreatic neuroendocrine tumors (GEPNETs) and small cell lung carcinomas (SCLCs). PCPG immune signature was validated with NanoString immune panel in an independent cohort. Unsupervised clustering of the immune infiltration scores from CIBERSORT was used to find immune clusters. A prognostic immune score model for PCPGs and the other NENs were calculated as a linear combination of the estimated infiltration of activated CD8+/CD4+ T cells, activated NK cells, and M0 and M2 macrophages. RESULTS In PCPGs, we found five dominant immune clusters, associated with M2 macrophages, monocytes, activated NK cells, M0 macrophages and regulatory T cells, and CD8+/CD4+ T cells respectively. Non-metastatic tumors were associated with activated NK cells and metastatic tumors were associated with M0 macrophages and regulatory T cells. In GEPNETs and SCLCs, M0 macrophages and regulatory T cells were associated with unfavorable outcomes and features, such as metastasis and high-grade tumors. The prognostic immune score model for PCPGs and the NENs could predict non-aggressive and non-metastatic diseases. In PCPGs, the immune score was also an independent predictor of metastasis-free survival in a multivariate Cox regression analysis. CONCLUSION The transcriptomic immune signature in PCPG correlates with clinical features like metastasis and prognosis.
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Affiliation(s)
- Suman Ghosal
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Katerina Hadrava Vanova
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ondrej Uher
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
- Department of Medical Biology, Faculty of Science, University of South Bohemia, Ceske Budejovice, 37005, Czech Republic
| | - Shaoli Das
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Mayank Patel
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Leah Meuter
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Thanh-Truc Huynh
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Sara Talvacchio
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Marianne Knue
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Tamara Prodanov
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Martha A Zeiger
- Office of Surgeon Scientists Programs, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Naris Nilubol
- Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - David Taieb
- Department of Nuclear Medicine, La Timone University Hospital, Aix-Marseille University, Marseille, France
- European Center for Research in Medical Imaging, Aix-Marseille University, Marseille, France
| | - Joakim Crona
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
- Department of Medical Sciences, Uppsala University, Akademiska Sjukhuset ing 78, 75185, Uppsala, Sweden
| | - Uma T Shankavaram
- Radiation Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
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18
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Long M, Wang J, Yang M. Transcriptomic Profiling of Breast Cancer Cells Induced by Tumor-Associated Macrophages Generates a Robust Prognostic Gene Signature. Cancers (Basel) 2022; 14:5364. [PMID: 36358783 PMCID: PMC9655582 DOI: 10.3390/cancers14215364] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 10/24/2022] [Accepted: 10/26/2022] [Indexed: 02/05/2024] Open
Abstract
Breast cancer, one of the most prevalent neoplasms in the world, continues attracting worldwide attention. Macrophage, as the most abundant non-malignant cell in tumor, plays critical roles in both immune surveillance and tumorigenesis and has become a cell target of immunotherapy. Among all macrophages, tumor-associated macrophage (TAM) is regarded as the main force to promote tumorigenesis. To get an overall view of its impact on breast cancer, we employed a simplified and indirect coculturing cell model followed by RNA-sequencing to detect cancer cell's transcriptomic response induced by TAM and a prognostic gene signature was constructed based on it. Evidence from both cell models and clinical samples strengthened TAM's full-dimensional impact on breast cancer, involved in almost all known signal pathways dysregulated during tumorigenesis from transcription, translation and molecule transport to immune-related pathways. Consequently, the gene signature developed from these genes was tested to be powerful in prognostic prediction and associated with various clinical and biological features of breast cancer. Our study presented a more complete view of TAM's impact on breast cancer, which strengthened its role as an important therapy target. A 45-gene signature from the TAM-regulated genes was developed and shown potential in clinical application.
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Affiliation(s)
- Meijun Long
- Breast Cancer Center, Department of Thyroid and Breast Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Jiajie Wang
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha 410011, China
| | - Mei Yang
- Hunan Key Laboratory of Tumor Models and Individualized Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, China
- Department of Orthopedics, The Second Xiangya Hospital, Central South University, Changsha 410011, China
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Amer HT, Eissa RA, El Tayebi HM. A cutting-edge immunomodulatory interlinkage between HOTAIR and MALAT1 in tumor-associated macrophages in breast cancer: A personalized immunotherapeutic approach. Front Mol Biosci 2022; 9:1032517. [PMID: 36387279 PMCID: PMC9649622 DOI: 10.3389/fmolb.2022.1032517] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 10/10/2022] [Indexed: 07/30/2023] Open
Abstract
Breast cancer (BC) is one of the most common cancers, accounting for 2.3 million cases worldwide. BC can be molecularly subclassified into luminal A, luminal B HER2-, luminal B HER2+, HER2+, and triple-negative breast cancer (TNBC). These molecular subtypes differ in their prognosis and treatment strategies; thus, understanding the tumor microenvironment (TME) of BC could lead to new potential treatment strategies. The TME hosts a population of cells that act as antitumorigenic such as tumor-associated eosinophils or pro-tumorigenic such as cancer-associated fibroblasts (CAFs), tumor-associated neutrophils (TANs), monocytic-derived populations such as MDSCs, or most importantly "tumor-associated macrophages (TAMs)," which are derived from CD14+ monocytes. TAMs are reported to have the pro-inflammatory phenotype M1, which is found only in the very early stages of tumor and is not correlated with progression; however, the M2 phenotype is anti-inflammatory that is correlated with tumor progression and metastasis. The current study focused on controlling the anti-inflammatory activity in TAMs of hormonal, HER2+, and TNBC by epigenetic fine-tuning of two immunomodulatory proteins, namely, CD80 and mesothelin (MSLN), which are known to be overexpressed in BC with pro-tumorigenic activity. Long non-coding RNAs are crucial key players in tumor progression whether acting as oncogenic or tumor suppressors. We focused on the regulatory role of MALAT1 and HOTAIR lncRNAs and their role in controlling the tumorigenic activity of TAMs. This study observed the impact of manipulation of MALAT1 and HOTAIR on the expression of both CD80 and MSLN in TAMs of BC. Moreover, we analyzed the interlinkage between HOTAIR and MALAT1 as regulators to one another in TAMs of BC. The current study reported an upstream regulatory effect of HOTAIR on MALAT1. Moreover, our results showed a promising use of MALAT1 and HOTAIR in regulating oncogenic immune-modulatory proteins MSLN and CD80 in TAMs of HER2+ and TNBC. The downregulation of MALAT1 and HOTAIR resulted in the upregulation of CD80 and MSLN, which indicates that they might have a cell-specific activity in TAMs. These data shed light on novel key players affecting the anti-inflammatory activity of TAMs as a possible therapeutic target in HER2+ and TNBC.
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Affiliation(s)
- Hoda T. Amer
- Department of Pharmacology and Toxicology, The Molecular Pharmacology Research Group, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
| | - Reda A. Eissa
- Department of Surgery, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | - Hend M. El Tayebi
- Department of Pharmacology and Toxicology, The Molecular Pharmacology Research Group, Faculty of Pharmacy and Biotechnology, German University in Cairo, Cairo, Egypt
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20
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Filiberti S, Russo M, Lonardi S, Bugatti M, Vermi W, Tournier C, Giurisato E. Self-Renewal of Macrophages: Tumor-Released Factors and Signaling Pathways. Biomedicines 2022; 10:2709. [PMID: 36359228 PMCID: PMC9687165 DOI: 10.3390/biomedicines10112709] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/14/2022] [Accepted: 10/21/2022] [Indexed: 04/11/2024] Open
Abstract
Macrophages are the most abundant immune cells of the tumor microenvironment (TME) and have multiple important functions in cancer. During tumor growth, both tissue-resident macrophages and newly recruited monocyte-derived macrophages can give rise to tumor-associated macrophages (TAMs), which have been associated with poor prognosis in most cancers. Compelling evidence indicate that the high degree of plasticity of macrophages and their ability to self-renew majorly impact tumor progression and resistance to therapy. In addition, the microenvironmental factors largely affect the metabolism of macrophages and may have a major influence on TAMs proliferation and subsets functions. Thus, understanding the signaling pathways regulating TAMs self-renewal capacity may help to identify promising targets for the development of novel anticancer agents. In this review, we focus on the environmental factors that promote the capacity of macrophages to self-renew and the molecular mechanisms that govern TAMs proliferation. We also highlight the impact of tumor-derived factors on macrophages metabolism and how distinct metabolic pathways affect macrophage self-renewal.
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Affiliation(s)
- Serena Filiberti
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | - Mariapia Russo
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
| | - Silvia Lonardi
- Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy
| | - Mattia Bugatti
- Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy
| | - William Vermi
- Department of Molecular and Translational Medicine, University of Brescia, 25100 Brescia, Italy
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA
| | - Cathy Tournier
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
| | - Emanuele Giurisato
- Department of Biotechnology Chemistry and Pharmacy, University of Siena, 53100 Siena, Italy
- Division of Cancer Sciences, School of Medical Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester M13 9PL, UK
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21
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Xie T, Fu DJ, Li ZM, Lv DJ, Song XL, Yu YZ, Wang C, Li KJ, Zhai B, Wu J, Feng NH, Zhao SC. CircSMARCC1 facilitates tumor progression by disrupting the crosstalk between prostate cancer cells and tumor-associated macrophages via miR-1322/CCL20/CCR6 signaling. Mol Cancer 2022; 21:173. [PMID: 36045408 PMCID: PMC9434883 DOI: 10.1186/s12943-022-01630-9] [Citation(s) in RCA: 60] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 07/25/2022] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) mediate the infiltration of tumor-associated macrophages (TAMs) to facilitate carcinogenesis and development of various types of cancers. However, the role of circRNAs in regulating macrophages in prostate cancer (PCa) remains uncertain. METHODS Differentially expressed circRNAs in PCa were identified by RNA sequencing. The expression of circSMARCC1 was recognized and evaluated using fluorescence in situ hybridization and quantitative real-time PCR. The oncogenic role of circSMARCC1 in PCa tumor proliferation and metastasis was investigated through a series of in vitro and in vivo assays. Finally, Western blot, biotin-labeled RNA pulldown, luciferase assay, rescue experiments, and co-culture experiments with TAMs were conducted to reveal the mechanistic role of circSMARCC1. RESULTS CircSMARCC1 was dramatically up-regulated in PCa cells, plasma and tissues. Overexpression of circSMARCC1 promotes tumor proliferation and metastasis both in vitro and in vivo, whereas knockdown of circSMARCC1 exerts the opposite effects. Mechanistically, circSMARCC1 regulates the expression of CC-chemokine ligand 20 (CCL20) via sponging miR-1322 and activate PI3K-Akt signaling pathway involved in the proliferation and epithelial mesenchymal transformation. More importantly, high expression of circSMARCC1 was positively associated with colonization of CD68+/CD163+/CD206+ TAMs in tumor microenvironment. In addition, overexpression of circSMARCC1 facilitates the expression of CD163 in macrophages through the CCL20-CCR6 axis, induces TAMs infiltration and M2 polarization, thereby leading to PCa progression. CONCLUSIONS CircSMARCC1 up-regulates the chemokine CCL20 secretion by sponging miR-1322, which is involved in the crosstalk between tumor cells and TAMs by targeting CCL20/CCR6 signaling to promote progression of PCa.
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Affiliation(s)
- Tao Xie
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, 510500, China
| | - Du-Jiang Fu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Zhi-Min Li
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Dao-Jun Lv
- Department of Urology, the Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China
| | - Xian-Lu Song
- Department of Radiotherapy, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
| | - Yu-Zhong Yu
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
- Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, 510500, China
| | - Chong Wang
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Kang-Jin Li
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Baoqian Zhai
- Department of Radiotherapy Oncology, Yancheng City No.1 People's Hospital, Yancheng, 224005, China
- The Fourth Affiliated Hospital of Nantong University, Yancheng, 224005, China
| | - Jiacheng Wu
- Department of Urology, Affiliated Tumor Hospital of Nantong University & Nantong Tumor Hospital, No. 30 Tongyang bei Road, Tongzhou District, Nantong, 226361, China.
| | - Ning-Han Feng
- Department of Urology, Affiliated Wuxi No. 2 Hospital, Nanjing Medical University, Wuxi, 214002, China.
| | - Shan-Chao Zhao
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
- Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, 510500, China.
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22
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Wang C, Lin Y, Zhu H, Zhou Y, Mao F, Huang X, Sun Q, Li C. The Prognostic and Clinical Value of Tumor-Associated Macrophages in Patients With Breast Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2022; 12:905846. [PMID: 35847911 PMCID: PMC9280493 DOI: 10.3389/fonc.2022.905846] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 05/26/2022] [Indexed: 12/24/2022] Open
Abstract
Background The prognostic and clinical value of tumor-associated macrophages (TAMs) in patients with breast cancer (BCa) remains unclear. We conducted the current meta-analysis to systematically evaluate the association of CD68+ and CD163+ TAM density with the prognosis and clinicopathologic features of BCa patients. Methods Searches of Web of Science, PubMed, and EMBASE databases were performed up to January 31, 2022. The meta-analysis was conducted using hazard risks (HRs) and 95% confidence intervals (CIs) for survival data including overall survival (OS), disease-free survival (DFS), and BCa specific survival. Sensitivity and meta-regression analyses were also conducted to identify the robustness of the pooled estimates. Results Our literature search identified relevant articles involving a total of 8,496 patients from 32 included studies. Our analysis indicates that a high CD68+ TAM density in the tumor stoma was significantly linked with poor OS (HR 2.46, 95% CI, 1.83–3.31, P<0.001) and shorter DFS (HR 1.77, 95% CI, 1.08–2.89, P=0.02) compared to low CD68+ TAM density. A significant association was also found in the tumor nest. Analysis of CD163+ TAM density showed similar results (all P<0.001). Notably, the pooled analysis with multivariate-adjusted HRs for OS and DFS also found that a high TAM density was significantly related to poorer outcomes for BCa patients (all P<0.05). In addition, BCa patients with high TAM density were more likely to have larger tumors, no vascular invasion, and positive estrogen receptor expression (all P<0.05). Conclusion This meta-analysis indicates that a high CD68+ and CD163+ TAM density is associated with poor OS and shorter DFS in BCa patients. Further clinical studies and in vivo experiments are needed to elucidate the underlying mechanism of TAMs. Systematic Review Registration https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022304853, identifier CRD42022304853.
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Affiliation(s)
- Changjun Wang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Yan Lin
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Hanjiang Zhu
- Department of Dermatology, 90 Medical Center Way, Surge 110, University of California, San Francisco, San Francisco, CA, United States
| | - Yidong Zhou
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Feng Mao
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Xin Huang
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
| | - Qiang Sun
- Department of Breast Surgery, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Qiang Sun, ; Chenggang Li,
| | - Chenggang Li
- State Key Laboratory of Medicinal Chemical biology, Nankai University, Tianjin, China
- College of Pharmacy, Nankai University, Tianjin, China
- *Correspondence: Qiang Sun, ; Chenggang Li,
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23
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Russo M, Nastasi C. Targeting the Tumor Microenvironment: A Close Up of Tumor-Associated Macrophages and Neutrophils. Front Oncol 2022; 12:871513. [PMID: 35664746 PMCID: PMC9160747 DOI: 10.3389/fonc.2022.871513] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Accepted: 04/11/2022] [Indexed: 12/15/2022] Open
Abstract
The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing the therapeutic outcome is widely accepted and appreciated. Several therapeutic strategies to modify or modulate the TME, like angiogenesis or immune checkpoint inhibitors, showed clinical efficacy and received approval from regulatory authorities. Within recent decades, new promising strategies targeting myeloid cells have been implemented in preclinical cancer models. The predominance of specific cell phenotypes in the TME has been attributed to pro- or anti-tumoral. Hence, their modulation can, in turn, alter the responses to standard-of-care treatments, making them more or less effective. Here, we summarize and discuss the current knowledge and the correlated challenges about the tumor-associated macrophages and neutrophils targeting strategies, current treatments, and future developments.
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Affiliation(s)
- Massimo Russo
- Laboratory of Cancer Metastasis Therapeutics, Department of Oncology, Mario Negri Pharmacological Research Institute (IRCCS), Milan, Italy
| | - Claudia Nastasi
- Laboratory of Cancer Pharmacology, Department of Oncology, Mario Negri Pharmacological Research Institute (IRCCS), Milan, Italy
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24
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Holterhus M, Altvater B, Kailayangiri S, Rossig C. The Cellular Tumor Immune Microenvironment of Childhood Solid Cancers: Informing More Effective Immunotherapies. Cancers (Basel) 2022; 14:cancers14092177. [PMID: 35565307 PMCID: PMC9105669 DOI: 10.3390/cancers14092177] [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: 03/08/2022] [Revised: 04/24/2022] [Accepted: 04/25/2022] [Indexed: 11/16/2022] Open
Abstract
Common pediatric solid cancers fail to respond to standard immuno-oncology agents relying on preexisting adaptive antitumor immune responses. The adoptive transfer of tumor-antigen specific T cells, such as CAR-gene modified T cells, is an attractive strategy, but its efficacy has been limited. Evidence is accumulating that local barriers in the tumor microenvironment prevent the infiltration of T cells and impede therapeutic immune responses. A thorough understanding of the components of the functional compartment of the tumor microenvironment and their interaction could inform effective combination therapies and novel engineered therapeutics, driving immunotherapy towards its full potential in pediatric patients. This review summarizes current knowledge on the cellular composition and significance of the tumor microenvironment in common extracranial solid cancers of childhood and adolescence, such as embryonal tumors and bone and soft tissue sarcomas, with a focus on myeloid cell populations that are often present in abundance in these tumors. Strategies to (co)target immunosuppressive myeloid cell populations with pharmacological anticancer agents and with selective antagonists are presented, as well as novel concepts aiming to employ myeloid cells to cooperate with antitumor T cell responses.
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25
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Molecular sensors for detection of tumor-stroma crosstalk. Adv Cancer Res 2022; 154:47-91. [PMID: 35459472 DOI: 10.1016/bs.acr.2022.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In most solid tumors, malignant cells coexist with non-cancerous host tissue comprised of a variety of extracellular matrix components and cell types, notably fibroblasts, immune cells, and endothelial cells. It is becoming increasingly evident that the non-cancerous host tissue, often referred to as the tumor stroma or the tumor microenvironment, wields tremendous influence in the proliferation, survival, and metastatic ability of cancer cells. The tumor stroma has an active biological role in the transmission of signals, such as growth factors and chemokines that activate oncogenic signaling pathways by autocrine and paracrine mechanisms. Moreover, the constituents of the stroma define the mechanical properties and the physical features of solid tumors, which influence cancer progression and response to therapy. Inspired by the emerging importance of tumor-stroma crosstalk and oncogenic physical forces, numerous biosensors, or advanced imaging and analysis techniques have been developed and applied to investigate complex and challenging questions in cancer research. These techniques facilitate measurements and biological readouts at scales ranging from subcellular to tissue-level with unprecedented level of spatial and temporal precision. Here we examine the application of biosensor technology for studying the complex and dynamic multiscale interactions of the tumor-host system.
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26
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Single-cell proteomics defines the cellular heterogeneity of localized prostate cancer. Cell Rep Med 2022; 3:100604. [PMID: 35492239 PMCID: PMC9044103 DOI: 10.1016/j.xcrm.2022.100604] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 12/30/2021] [Accepted: 03/21/2022] [Indexed: 11/16/2022]
Abstract
Localized prostate cancer exhibits multiple genomic alterations and heterogeneity at the proteomic level. Single-cell technologies capture important cell-to-cell variability responsible for heterogeneity in biomarker expression that may be overlooked when molecular alterations are based on bulk tissue samples. This study aims to identify prognostic biomarkers and describe the heterogeneity of prostate cancer and the associated microenvironment by simultaneously quantifying 36 proteins using single-cell mass cytometry analysis of over 1.6 million cells from 58 men with localized prostate cancer. We perform this task, using a high-dimensional clustering pipeline named Franken to describe subpopulations of immune, stromal, and prostate cells, including changes occurring in tumor tissues and high-grade disease that provide insights into the coordinated progression of prostate cancer. Our results further indicate that men with localized disease already harbor rare subpopulations that typically occur in castration-resistant and metastatic disease.
Single-cell proteomics of localized prostate cancer defines disease heterogeneity Malignant and benign prostate tissues differ in rare cell-type proportional shifts T cells and proliferating macrophages are associated with high-grade PCa Rare CD15+ epithelial cells are amplified in high-grade PCa
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27
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Luo Y, Tao T, Tao R, Huang G, Wu S. Single-Cell Transcriptome Comparison of Bladder Cancer Reveals Its Ecosystem. Front Oncol 2022; 12:818147. [PMID: 35265520 PMCID: PMC8899594 DOI: 10.3389/fonc.2022.818147] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Accepted: 01/26/2022] [Indexed: 11/13/2022] Open
Abstract
Bladder carcinoma (BLCA) is a highly heterogeneous disease, and the underlying biological behavior is still poorly understood. Here, single-cell RNA sequencing was performed on four clinical samples of different grades from three patients, and 26,792 cell transcriptomes were obtained revealing different tumor ecosystems. We found that N-glycan biosynthesis pathway was activated in high-grade tumor, but TNF-related pathway was activated in cystitis glandularis. The tumor microenvironment (TME) of different samples showed great heterogeneity. Notably, cystitis glandularis was dominated by T cells, low-grade and high-grade tumors by macrophages, while TME in patient with high-grade relapse by stromal cells. Our research provides single-cell transcriptome profiles of cystitis glandularis and BLCA in different clinical states, and the biological program revealed by single-cell data can be used as biomarkers related to clinical prognosis in independent cohorts.
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Affiliation(s)
- Yongxiang Luo
- Institute of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China.,Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
| | - Tao Tao
- Institute of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China.,Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
| | - Ran Tao
- Institute of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
| | - Guixiao Huang
- Institute of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
| | - Song Wu
- Institute of Urological Surgery, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China.,Shenzhen Following Precision Medical Institute, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, China.,Department of Urology, The Affiliated South China Hospital of Shenzhen University, Shenzhen University, Shenzhen, China
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28
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Hadadi E, Deschoemaeker S, Vicente Venegas G, Laoui D. Heterogeneity and function of macrophages in the breast during homeostasis and cancer. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2022; 367:149-182. [PMID: 35461657 DOI: 10.1016/bs.ircmb.2022.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Macrophages are diverse immune cells populating all tissues and adopting a unique tissue-specific identity. Breast macrophages play an essential role in the development and function of the mammary gland over one's lifetime. In the recent years, with the development of fate-mapping, imaging and scRNA-seq technologies we grew a better understanding of the origin, heterogeneity and function of mammary macrophages in homeostasis but also during breast cancer development. Here, we aim to provide a comprehensive review of the latest improvements in studying the macrophage heterogeneity in healthy mammary tissues and breast cancer.
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Affiliation(s)
- Eva Hadadi
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Sofie Deschoemaeker
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Gerard Vicente Venegas
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium
| | - Damya Laoui
- Myeloid Cell Immunology Lab, VIB Center for Inflammation Research, Brussels, Belgium; Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.
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29
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Mishra S, Charan M, Shukla RK, Agarwal P, Misri S, Verma AK, Ahirwar DK, Siddiqui J, Kaul K, Sahu N, Vyas K, Garg AA, Khan A, Miles WO, Song JW, Bhutani N, Ganju RK. cPLA2 blockade attenuates S100A7-mediated breast tumorigenicity by inhibiting the immunosuppressive tumor microenvironment. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2022; 41:54. [PMID: 35135586 PMCID: PMC8822829 DOI: 10.1186/s13046-021-02221-0] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 12/11/2021] [Indexed: 02/04/2023]
Abstract
BACKGROUND Molecular mechanisms underlying inflammation-associated breast tumor growth are poorly studied. S100A7, a pro-inflammatory molecule has been shown to enhance breast cancer growth and metastasis. However, the S100A7-mediated molecular mechanisms in enhancing tumor growth and metastasis are unclear. METHODS Human breast cancer tissue and plasma samples were used to analyze the expression of S100A7, cPLA2, and PGE2. S100A7-overexpressing or downregulated human metastatic breast cancer cells were used to evaluate the S100A7-mediated downstream signaling mechanisms. Bi-transgenic mS100a7a15 overexpression, TNBC C3 (1)/Tag transgenic, and humanized patient-derived xenograft mouse models and cPLA2 inhibitor (AACOCF3) were used to investigate the role of S100A7/cPLA2/PGE2 signaling in tumor growth and metastasis. Additionally, CODEX, a highly advanced multiplexed imaging was employed to delineate the effects of S100A7/cPLA2 inhibition on the recruitment of various immune cells. RESULTS In this study, we found that S100A7 and cPLA2 are highly expressed and correlate with decreased overall survival in breast cancer patients. Further mechanistic studies revealed that S100A7/RAGE signaling promotes the expression of cPLA2 to mediate its oncogenic effects. Pharmacological inhibition of cPLA2 suppressed S100A7-mediated tumor growth and metastasis in multiple pre-clinical models including transgenic and humanized patient-derived xenograft (PDX) mouse models. The attenuation of cPLA2 signaling reduced S100A7-mediated recruitment of immune-suppressive myeloid cells in the tumor microenvironment (TME). Interestingly, we discovered that the S100A7/cPLA2 axis enhances the immunosuppressive microenvironment by increasing prostaglandin E2 (PGE2). Furthermore, CO-Detection by indEXing (CODEX) imaging-based analyses revealed that cPLA2 inhibition increased the infiltration of activated and proliferating CD4+ and CD8+ T cells in the TME. In addition, CD163+ tumor associated-macrophages were positively associated with S100A7 and cPLA2 expression in malignant breast cancer patients. CONCLUSIONS Our study provides new mechanistic insights on the cross-talk between S100A7/cPLA2 in enhancing breast tumor growth and metastasis by generating an immunosuppressive TME that inhibits the infiltration of cytotoxic T cells. Furthermore, our studies indicate that S100A7/cPLA2 could be used as novel prognostic marker and cPLA2 inhibitors as promising drugs against S100A7-overexpressing aggressive breast cancer.
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Affiliation(s)
- Sanjay Mishra
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
| | - Manish Charan
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
| | - Rajni Kant Shukla
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Department of Microbial, Infection & Immunity, The Ohio State University, Columbus, OH 43210 USA
| | - Pranay Agarwal
- grid.168010.e0000000419368956Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94305 USA
| | - Swati Misri
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
| | - Ajeet K. Verma
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
| | - Dinesh K. Ahirwar
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
| | - Jalal Siddiqui
- grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210 USA
| | - Kirti Kaul
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
| | - Neety Sahu
- grid.168010.e0000000419368956Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94305 USA
| | - Kunj Vyas
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
| | - Ayush Arpit Garg
- grid.261331.40000 0001 2285 7943Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH 43210 USA
| | - Anum Khan
- grid.168010.e0000000419368956School of Medicine, Cell Science Imaging Facility, Stanford University, Stanford, CA 94305 USA
| | - Wayne O. Miles
- grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH 43210 USA
| | - Jonathan W. Song
- grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Department of Mechanical and Aerospace Engineering, The Ohio State University, Columbus, OH 43210 USA
| | - Nidhi Bhutani
- grid.168010.e0000000419368956Department of Orthopaedic Surgery, Stanford University, Stanford, CA 94305 USA
| | - Ramesh K. Ganju
- grid.261331.40000 0001 2285 7943Department of Pathology, College of Medicine, The Ohio State University, Columbus, OH 43210 USA ,grid.261331.40000 0001 2285 7943Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210 USA
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Yin Y, Zhang Y, Li L, Zhang S, Liu N, Yuan S. Prognostic Value of Pretreatment Lymphocyte-to-Monocyte Ratio and Development of a Nomogram in Breast Cancer Patients. Front Oncol 2021; 11:650980. [PMID: 34976782 PMCID: PMC8719671 DOI: 10.3389/fonc.2021.650980] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 11/30/2021] [Indexed: 11/19/2022] Open
Abstract
Purpose The objective of this study was to explore the prognostic significance of pretreatment hematologic parameters in predicting disease-free survival (DFS) of breast cancer patients. Materials and Methods The medical records of 440 breast cancer patients in Shandong Cancer Hospital and Institute from 2003 to 2013 were analyzed retrospectively. Through the results of blood routine before treatment, the absolute lymphocyte count (ALC), absolute neutrophil count (ANC), absolute monocyte count (AMC), and absolute platelet count (APC) in peripheral blood were collected. The lymphocyte-to-monocyte ratio (LMR), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-monocyte ratio (NMR) were calculated. Cox proportional hazard model was used for univariate and multivariate analysis. The DFS was compared using Kaplan–Meier method. The prognostic nomogram of patients with breast cancer was developed. Results The median DFS for all patients was 64.10 months. Univariate analysis showed that the DFS was associated with surgical approach, TNM stage, molecular subtype, neoadjuvant chemotherapy, radiotherapy, and LMR (p < 0.05). TNM stage, molecular subtype, and LMR were independent prognostic factors of breast cancer in multivariate analysis (p < 0.05). According to the Kaplan–Meier survival curve analysis, patients with higher LMR (≥4.85) were associated with longer median DFS (median DFS, 85.83 vs. 60.90, p < 0.001). The proposed nomogram that incorporated LMR, TNM stage, and molecular subtype got a concordance index (c-index) of 0.69 in predicting 5-year DFS. Conclusion In breast cancer patients, higher LMR was associated with longer median DFS and the nomogram including LMR, TNM stage, and molecular subtype could accurately predict the prolonged 5-year DFS of breast cancer patients.
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Affiliation(s)
- Ying Yin
- Clinical Medical College, Southwest Medical University, Luzhou, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yong Zhang
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Radiation Oncology, Rongcheng People's Hospital, Rongcheng, China
| | - Li Li
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shaotong Zhang
- Department of Ultrasound, Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Ning Liu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shuanghu Yuan
- Clinical Medical College, Southwest Medical University, Luzhou, China
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Shandong Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China
- Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
- *Correspondence: Shuanghu Yuan,
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31
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Osborn G, Stavraka C, Adams R, Sayasneh A, Ghosh S, Montes A, Lacy KE, Kristeleit R, Spicer J, Josephs DH, Arnold JN, Karagiannis SN. Macrophages in ovarian cancer and their interactions with monoclonal antibody therapies. Clin Exp Immunol 2021; 209:4-21. [PMID: 35020853 PMCID: PMC9307234 DOI: 10.1093/cei/uxab020] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 10/26/2021] [Accepted: 11/19/2021] [Indexed: 12/31/2022] Open
Abstract
Abstract
The unmet clinical need for effective treatments in ovarian cancer has yet to be addressed using monoclonal antibodies (mAbs), which have largely failed to overcome tumour-associated immunosuppression, restrict cancer growth, and significantly improve survival. In recent years, experimental mAb design has moved away from solely targeting ovarian tumours and instead sought to modulate the wider tumour microenvironment (TME). Tumour-associated macrophages (TAMs) may represent an attractive therapeutic target for mAbs in ovarian cancer due to their high abundance and close proximity to tumour cells and their active involvement in facilitating several pro-tumoural processes. Moreover, the expression of several antibody crystallisable fragment (Fc) receptors and broad phenotypic plasticity of TAMs provide opportunities to modulate TAM polarisation using mAbs to promote anti-tumoural phenotypes. In this review, we discuss the role of TAMs in ovarian cancer TME and the emerging strategies to target the contributions of these cells in tumour progression through the rationale design of mAbs.
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Affiliation(s)
- Gabriel Osborn
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, United Kingdom
| | - Chara Stavraka
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, United Kingdom.,Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.,School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Rebecca Adams
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, United Kingdom
| | - Ahmad Sayasneh
- Department of Gynecological Oncology, Surgical Oncology Directorate, Guy's and St Thomas' NHS Foundation Trust, School of Life Course Sciences, King's College London, London, United Kingdom
| | - Sharmistha Ghosh
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Ana Montes
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - Katie E Lacy
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, United Kingdom
| | - Rebecca Kristeleit
- Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom
| | - James Spicer
- School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Debra H Josephs
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, United Kingdom.,Cancer Centre at Guy's, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.,School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - James N Arnold
- School of Cancer & Pharmaceutical Sciences, King's College London, London, United Kingdom
| | - Sophia N Karagiannis
- St. John's Institute of Dermatology, School of Basic & Medical Biosciences, King's College London, London, United Kingdom.,Breast Cancer Now Research Unit, School of Cancer & Pharmaceutical Sciences, King's College London, Guy's Cancer Centre, London, United Kingdom
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Batoon L, McCauley LK. Cross Talk Between Macrophages and Cancer Cells in the Bone Metastatic Environment. Front Endocrinol (Lausanne) 2021; 12:763846. [PMID: 34803925 PMCID: PMC8597897 DOI: 10.3389/fendo.2021.763846] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 10/11/2021] [Indexed: 12/12/2022] Open
Abstract
The skeleton is a common site for cancer metastases with the bone microenvironment providing the appropriate conditions for cancer cell colonization. Once in bone, cancer cells effectively manipulate their microenvironment to support their growth and survival. Despite previous efforts to improve treatment modalities, skeletal metastases remain with poor prognoses. This warrants an improved understanding of the mechanisms leading to bone metastasis that will aid development of effective treatments. Macrophages in the tumor microenvironment are termed tumor associated macrophages (TAMs) and their crosstalk with cancer cells is critical in regulating tumorigenicity in multiple cancers. In bone metastases, this crosstalk is also being increasingly implicated but the specific signaling pathways remain incompletely understood. Here, we summarize the reported functions, interactions, and signaling of macrophages with cancer cells during the metastatic cascade to bone. Specifically, we review and discuss how these specific interactions impact macrophages and their profiles to promote tumor development. We also discuss the potential of targeting this crosstalk to inhibit disease progression. Finally, we identify the remaining knowledge gaps that will need to be addressed in order to fully consider therapeutic targeting to improve clinical outcomes in cancer patients.
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Affiliation(s)
- Lena Batoon
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
- Bones and Immunology Group, Mater Research Institute, The University of Queensland, Brisbane, QLD, Australia
| | - Laurie K. McCauley
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
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Sex-Based Differences in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1329:499-533. [PMID: 34664253 DOI: 10.1007/978-3-030-73119-9_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/20/2023]
Abstract
Cancers are heterogeneous multifactorial diseases consisting of a major public health issue worldwide. Sex disparities are evidenced in cancer incidence, mortality, expression of prognosis factor, response to treatment, and survival. For both sexes, an interplay of intrinsic and environmental factors influences cancer cells and tumor microenvironment (TME) components. The TME cumulates both supportive and communicative functions, contributing to cancer development, progression, and metastasis dissemination. The frontline topics of this chapter are focused on the contribution of sex, via steroid hormones, such as estrogens and androgens, on the following components of the TME: cancer-associated fibroblasts (CAFs), extracellular matrix (ECM), blood and lymphatic endothelial cells, and immunity/inflammatory system.
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Figueiredo P, Lepland A, Scodeller P, Fontana F, Torrieri G, Tiboni M, Shahbazi MA, Casettari L, Kostiainen MA, Hirvonen J, Teesalu T, Santos HA. Peptide-guided resiquimod-loaded lignin nanoparticles convert tumor-associated macrophages from M2 to M1 phenotype for enhanced chemotherapy. Acta Biomater 2021; 133:231-243. [PMID: 33011297 DOI: 10.1016/j.actbio.2020.09.038] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/23/2020] [Accepted: 09/24/2020] [Indexed: 02/06/2023]
Abstract
Nanomedicines represent innovative and promising alternative technologies to improve the therapeutic effects of different drugs for cancer ablation. Targeting M2-like tumor-associated macrophages (TAMs) has emerged as a favorable therapeutic approach to fight against cancer through the modulation of the tumor microenvironment. However, the immunomodulatory molecules used for this purpose present side effects upon systemic administration, which limits their clinical translation. Here, the biocompatible lignin polymer is used to prepare lignin nanoparticles (LNPs) that carry a dual agonist of the toll-like receptors TLR7/8 (resiquimod, R848). These LNPs are targeted to the CD206-positive M2-like TAMs using the "mUNO" peptide, in order to revert their pro-tumor phenotype into anti-tumor M1-like macrophages in the tumor microenvironment of an aggressive triple-negative in vivo model of breast cancer. Overall, we show that targeting the resiquimod (R848)-loaded LNPs to the M2-like macrophages, using very low doses of R848, induces a profound shift in the immune cells in the tumor microenvironment towards an anti-tumor immune state, by increasing the representation of M1-like macrophages, cytotoxic T cells, and activated dendritic cells. This effect consequently enhances the anticancer effect of the vinblastine (Vin) when co-administered with R848-loaded LNPs. STATEMENT OF SIGNIFICANCE: Lignin-based nanoparticles (LNPs) were successfully developed to target a potent TLR7/8 agonist (R848) of the tumor microenvironment (TME). This was achieved by targeting the mannose receptor (CD206) on the tumor supportive (M2-like) macrophages with the "mUNO" peptide, to reprogram them into an anti-tumor (M1-like) phenotype for enhanced chemotherapy. LNPs modified the biodistribution of the R848, and enhanced its accumulation and efficacy in shifting the immunological profile of the cells in the TME, which was not achieved by systemic administration of free R848. Moreover, a reduction in the tumor volumes was observed at lower equivalent doses of R848 compared with other studies. Therefore, the co-administration of R848@LNPs is a promising chemotherapeutic application in aggressive tumors, such as the triple-negative breast cancer.
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Affiliation(s)
- Patrícia Figueiredo
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland.
| | - Anni Lepland
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Pablo Scodeller
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia.
| | - Flavia Fontana
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland
| | - Giulia Torrieri
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland
| | - Mattia Tiboni
- Department of Biomolecular Sciences, School of Pharmacy, University of Urbino Carlo Bo, Urbino, Italy
| | - Mohammad-Ali Shahbazi
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Zanjan University of Medical Sciences, 56184-45139 Zanjan, Iran
| | - Luca Casettari
- Department of Biomolecular Sciences, School of Pharmacy, University of Urbino Carlo Bo, Urbino, Italy
| | - Mauri A Kostiainen
- Biohybrid Materials, Department of Bioproducts and Biosystems, Aalto University, FI-00076, Aalto, Finland
| | - Jouni Hirvonen
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland
| | - Tambet Teesalu
- Laboratory of Cancer Biology, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia; Center for Nanomedicine and Department of Cell, Molecular and Developmental Biology, University of California, Santa Barbara, 93106, CA, USA; Cancer Research Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, 92037, CA, USA.
| | - Hélder A Santos
- Drug Research Program, Division of Pharmaceutical Chemistry and Technology, Faculty of Pharmacy, University of Helsinki, FI-00014 Helsinki, Finland; Helsinki Institute of Life Science (HiLIFE), University of Helsinki, FI-00014 Helsinki, Finland.
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Han B, Wang T, Xue Z, Wen T, Lu L, Meng J, Liu J, Wu S, Yu J, Xu H. Elemene Nanoemulsion Inhibits Metastasis of Breast Cancer by ROS Scavenging. Int J Nanomedicine 2021; 16:6035-6048. [PMID: 34511904 PMCID: PMC8418379 DOI: 10.2147/ijn.s327094] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 08/19/2021] [Indexed: 12/19/2022] Open
Abstract
Introduction Elemene (C15H24) is a sesquiterpene compound extracted from the rhizome of Curcuma herbs. In the past decades, the anti-tumor activity of elemene has been observed in vitro and in some clinical practices. However, pharmacological mechanisms of elemene are not demonstrated adequately, which may lead to improper clinical applications. This study aimed to investigate the anti-tumor effect of elemene nanoemulsion in the mouse model of triple-negative breast cancer (TNBC) and reveal the underlying mechanisms. Methods The ESR measurement and quantum mechanics simulation were used to characterize the antioxidant ability of elemene nanoemulsion. The murine breast cancer cell line 4T1 cells were inoculated subcutaneously into the left fourth mammary fat pad of BalB/c mice to establish a TNBC mice model. The H&E staining, immunohistochemical staining, DHE staining and Western blot were employed to evaluate the therapeutic effects of the elemene nanoemulsion on the TNBC mice. Results It was shown that the elemene nanoemulsion prolonged the survival of the triple-negative breast cancer-bearing mice and inhibited the metastasis to lung and liver while did not induce significant cytotoxicity to the tumor cells. Mechanistic studies demonstrated that the elemene nanoemulsion effectively scavenged the reactive oxygen species (ROS) in vitro and in vivo, which decreased the stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently reduced angiogenesis in the tumor microenvironment as well as decreased the level of NLRP3 inflammasomes and IL-1β production. In addition, the elemene nanoemulsion downregulated the level of IL-1β in the RAW264.7 cells in exposure with LPS. Conclusion In conclusion, due to the ROS scavenging ability, elemene nanoemulsion effectively inhibited the metastasis of the breast cancer cells to lung and liver and consequently prolonged the survival of TNBC mice.
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Affiliation(s)
- Bo Han
- Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People's Republic of China
| | - Tao Wang
- Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People's Republic of China
| | - Zhigang Xue
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Tao Wen
- Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People's Republic of China
| | - Ling Lu
- State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, People's Republic of China
| | - Jie Meng
- Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People's Republic of China
| | - Jian Liu
- Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People's Republic of China
| | - Sizhu Wu
- State Key Laboratory of Organic-Inorganic Composites, Beijing University of Chemical Technology, Beijing, People's Republic of China
| | - Jianchun Yu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People's Republic of China
| | - Haiyan Xu
- Department of Biomedical Engineering, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing, People's Republic of China
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Chamseddine AN, Assi T, Mir O, Chouaib S. Modulating tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors: A TAM-pting approach. Pharmacol Ther 2021; 231:107986. [PMID: 34481812 DOI: 10.1016/j.pharmthera.2021.107986] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 12/14/2022]
Abstract
Tumor-associated macrophages (TAM) plasticity and diversity are both essential hallmarks of the monocyte-macrophage lineage and the tumor-derived inflammation. TAM exemplify the perfect adaptable cell with dynamic phenotypic modifications that reflect changes in their functional polarization status. Under several tumor microenvironment (TME)-related cues, TAM shift their polarization, hence promoting or halting cancer progression. Immune checkpoint inhibitors (ICI) displayed unprecedented clinical responses in various refractory cancers; but only approximately a third of patients experienced durable responses. It is, therefore, crucial to enhance the response rate of immunotherapy. Several mechanisms of resistance to ICI have been elucidated including TAM role with its essential immunosuppressive functions that reduce both anti-tumor immunity and the subsequent ICI efficacy. In the past few years, thorough research has led to a better understanding of TAM biology and innovative approaches can now be adapted through targeting macrophages' recruitment axis as well as TAM activation and polarization status within the TME. Some of these therapeutic strategies are currently being evaluated in several clinical trials in association with ICI agents. This combination between TAM modulation and ICI allows targeting TAM intrinsic immunosuppressive functions and tumor-promoting factors as well as overcoming ICI resistance. Hence, such strategies, with a better understanding of the mechanisms driving TAM modulation, may have the potential to optimize ICI efficacy.
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Affiliation(s)
- Ali N Chamseddine
- Department of Medical Oncology, Gustave Roussy, F-94805, Villejuif, France; Department of Biostatistics and Epidemiology, CESP INSERM U1018, OncoStat, Gustave Roussy, F-94805, Villejuif, France.
| | - Tarek Assi
- Department of Medical Oncology, Gustave Roussy, F-94805, Villejuif, France
| | - Olivier Mir
- Department of Medical Oncology, Gustave Roussy, F-94805, Villejuif, France; Department of Pharmacology, Gustave Roussy, F-94805, Villejuif, France; Department of Ambulatory Care, Gustave Roussy, F-94805, Villejuif, France
| | - Salem Chouaib
- INSERM UMR 1186, Integrative Tumor Immunology and Genetic Oncology, Gustave Roussy, F-94805, Villejuif, France
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Yang WJ, Shi L, Wang XM, Yang GW. Heparanase is a novel biomarker for immune infiltration and prognosis in breast cancer. Aging (Albany NY) 2021; 13:20836-20852. [PMID: 34461608 PMCID: PMC8436937 DOI: 10.18632/aging.203489] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 04/29/2021] [Indexed: 04/28/2023]
Abstract
Heparanase (HPSE), an endoglycosidase that cleaves heparan sulfate, regulates a variety of biological processes that promote tumor progression. In this study, we analyzed the correlation between HPSE expression and prognosis in cancer patients, using multiple databases (Oncomine, TIMER, PrognoScan, GEPIA, Kaplan-Meier plotter, miner v4.1, DAVID). HPSE expression was significantly increased in bladder, breast, lung, and stomach cancer compared to matched normal tissues. The increased HPSE expression correlated with poor prognosis and increased immune infiltration levels of B cells, CD8+ and CD4+ T cells, macrophages, neutrophils and dendritic cells in bladder and breast cancer. In breast cancer, the high HPSE expression was associated with basal-like subtypes, younger age (0-40), advanced Scarff-Bloom-Richardson grade, Nottingham Prognostic Index and p53 mutation status. In addition, using a mouse model of breast cancer, our data showed that HPSE upregulated IL-10 expression and promoted macrophage M2 polarization and T cell exhaustion. Together, our data provide a novel immunological perspective on the mechanisms underlying breast cancer progression, and indicate that HPSE may serve as a biomarker for immune infiltration and prognosis in breast cancer.
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Affiliation(s)
- Wen-Jing Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Lin Shi
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Xiao-Min Wang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
| | - Guo-Wang Yang
- Department of Oncology, Beijing Hospital of Traditional Chinese Medicine, Capital Medical University, Beijing 100010, China
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Yang Y, He X, Tang QQ, Shao YC, Song WJ, Gong PJ, Zeng YF, Huang SR, Zhou JY, Wan HF, Wei L, Zhang JW. GMFG Has Potential to Be a Novel Prognostic Marker and Related to Immune Infiltrates in Breast Cancer. Front Oncol 2021; 11:629633. [PMID: 34367945 PMCID: PMC8343142 DOI: 10.3389/fonc.2021.629633] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 06/30/2021] [Indexed: 12/24/2022] Open
Abstract
A growing amount of evidence has indicated immune genes perform a crucial position in the development and progression of breast cancer microenvironment. The purpose of our study was to identify immunogenic prognostic marker and explore potential regulatory mechanisms for breast cancer. We identified the genes related to ImmuneScore using ESTIMATE algorithm and WGCNA analysis, and we identified the differentially expressed gene (DEGs). Then, Glia maturation factor γ (GMFG) was determined as a predictive factor by intersecting immune-related genes with DEGs and survival analysis. We found the expression of GMFG was lower in breast cancer tissues compared with normal breast tissues, which was further verified by immunohistochemical (IHC). Moreover, the decreased expression of GMFG was significantly related to the poor prognosis. Besides, the expression of GMFG was related to the age, ER status, PR status, HER2 status and tumor size, which further suggested that the expression of GMFG was correlated with the subtype and the growth of tumor. The univariate and multivariate Cox regression analyses revealed that age, stage, the expression level of GMFG and radiotherapy were independent factors for predicting the prognosis of breast cancer patients. Subsequently, a prognostic model to predict the 3-year, 5-year and 10-year overall survival rate was developed based on the above four variables, and visualized as a nomogram. The values of area under the curve of the nomogram at 3-year, 5-year and 10-year were 0.897, 0.873 and 0.922, respectively, which was higher than stage in prognostic accuracy. In addition, we also found that GMFG expression level was correlated with sensitivity of some breast cancer chemotherapy drugs. Furthermore, the results of GSEA indicated immune-related pathways were mainly enriched in GMFG-high-expression group. CIBERSORT analysis for the proportion of tumor-infiltrating immune cells (TIICs) suggested that expression of GMFG was positively association with multiple kinds T-cell in BC. Among them, CD8+ T cells had the strongest correlation with GMFG expression, which revealed that GMFG might has an antitumor effect by increasing the infiltration of CD8+ T cells in breast cancer. Accordingly, GMFG has the potential to become a novel immune biomarker for the diagnosis and treatment of breast cancer.
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Affiliation(s)
- Yan Yang
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Xin He
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Qian-Qian Tang
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - You-Cheng Shao
- Department of Pathology and Pathophysiology, School of Basic Medicine, Wuhan University, Wuhan, China
| | - Wen-Jing Song
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Peng-Ju Gong
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yi-Fan Zeng
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Si-Rui Huang
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Jiang-Yao Zhou
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Hui-Fang Wan
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Lei Wei
- Department of Pathology and Pathophysiology, School of Basic Medicine, Wuhan University, Wuhan, China
| | - Jing-Wei Zhang
- Department of Breast and Thyroid Surgery, Zhongnan Hospital, Wuhan University, Wuhan, China
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Yam C, Yen EY, Chang JT, Bassett RL, Alatrash G, Garber H, Huo L, Yang F, Philips AV, Ding QQ, Lim B, Ueno NT, Kannan K, Sun X, Sun B, Parra Cuentas ER, Symmans WF, White JB, Ravenberg E, Seth S, Guerriero JL, Rauch GM, Damodaran S, Litton JK, Wargo JA, Hortobagyi GN, Futreal A, Wistuba II, Sun R, Moulder SL, Mittendorf EA. Immune Phenotype and Response to Neoadjuvant Therapy in Triple-Negative Breast Cancer. Clin Cancer Res 2021; 27:5365-5375. [PMID: 34253579 DOI: 10.1158/1078-0432.ccr-21-0144] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 05/10/2021] [Accepted: 07/07/2021] [Indexed: 11/16/2022]
Abstract
PURPOSE Increasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR. EXPERIMENTAL DESIGN We obtained pretreatment core-needle biopsies from 105 patients with stage I-III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT. RESULTS The pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage. CONCLUSIONS In patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
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Affiliation(s)
- Clinton Yam
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Er-Yen Yen
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jeffrey T Chang
- Department of Integrative Biology and Pharmacology, The University of Texas Health Science Center at Houston, Houston, Texas
| | - Roland L Bassett
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gheath Alatrash
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Haven Garber
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lei Huo
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Fei Yang
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anne V Philips
- Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Qing-Qing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bora Lim
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Naoto T Ueno
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kasthuri Kannan
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Xiangjie Sun
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Baohua Sun
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Edwin Roger Parra Cuentas
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - William Fraser Symmans
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jason B White
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elizabeth Ravenberg
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sahil Seth
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer L Guerriero
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.,Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts
| | - Gaiane M Rauch
- Department of Diagnostic Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Senthil Damodaran
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer K Litton
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Jennifer A Wargo
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Gabriel N Hortobagyi
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Andrew Futreal
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ryan Sun
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Stacy L Moulder
- Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Elizabeth A Mittendorf
- Division of Breast Surgery, Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts. .,Breast Oncology Program, Dana-Farber/Brigham and Women's Cancer Center, Boston, Massachusetts.,Ludwig Center at Harvard, Boston, Massachusetts
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40
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Kojima M, Sugimoto K, Kobayashi M, Ichikawa-Tomikawa N, Kashiwagi K, Watanabe T, Soeda S, Fujimori K, Chiba H. Aberrant Claudin-6-Adhesion Signaling Promotes Endometrial Cancer Progression via Estrogen Receptor α. Mol Cancer Res 2021; 19:1208-1220. [PMID: 33727343 DOI: 10.1158/1541-7786.mcr-20-0835] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 01/04/2021] [Accepted: 03/11/2021] [Indexed: 11/16/2022]
Abstract
Cell adhesion proteins not only maintain tissue integrity, but also possess signaling abilities to organize diverse cellular events in a variety of physiologic and pathologic processes; however, the underlying mechanism remains obscure. Among cell adhesion molecules, the claudin (CLDN) family is often aberrantly expressed in various cancers, but the biological relevance and molecular basis for this observation have not yet been established. Here, we show that high CLDN6 expression accelerates cellular proliferation and migration in two distinct human endometrial cancer cell lines in vitro. Using a xenograft model, we also revealed that aberrant CLDN6 expression promotes tumor growth and invasion in endometrial cancer tissues. The second extracellular domain and Y196/200 of CLDN6 were required to recruit and activate Src-family kinases (SFK) and to stimulate malignant phenotypes. Knockout and overexpression of ESR1 in endometrial carcinoma cells showed that the CLDN6-adhesion signal links to estrogen receptor α (ERα) to advance tumor progression. In particular, aberrant CLDN6-ERα signaling contributed to collective cell behaviors in the leading front of endometrial cancer cells. Importantly, we demonstrate that CLDN6/SFK/PI3K-dependent AKT and SGK (serum- and glucocorticoid-regulated kinase) signaling in endometrial cancer cells targets Ser518 in the human ERα to activate ERα transcriptional activity in a ligand-independent manner, thereby promoting tumor progression. Furthermore, CLDN6, at least in part, also regulated gene expression in an ERα-independent manner. IMPLICATIONS: The identification of this machinery highlights regulation of the transcription factors by cell adhesion to advance tumor progression.
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Affiliation(s)
- Manabu Kojima
- Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan
- Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Kotaro Sugimoto
- Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
| | - Makoto Kobayashi
- Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Naoki Ichikawa-Tomikawa
- Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Korehito Kashiwagi
- Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Takafumi Watanabe
- Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Shu Soeda
- Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Keiya Fujimori
- Department of Obstetrics and Gynecology, Fukushima Medical University School of Medicine, Fukushima, Japan
| | - Hideki Chiba
- Department of Basic Pathology, Fukushima Medical University School of Medicine, Fukushima, Japan.
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41
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Glencer AC, Wong JM, Hylton NM, Krings G, McCune E, Rothschild HT, Loveday TA, Alvarado MD, Esserman LJ, Campbell MJ. Modulation of the immune microenvironment of high-risk ductal carcinoma in situ by intralesional pembrolizumab injection. NPJ Breast Cancer 2021; 7:59. [PMID: 34035311 PMCID: PMC8149838 DOI: 10.1038/s41523-021-00267-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Accepted: 04/19/2021] [Indexed: 12/31/2022] Open
Abstract
Ductal carcinoma in situ (DCIS) is a risk factor for the subsequent development of invasive breast cancer. High-risk features include age <45 years, size >5 cm, high-grade, palpable mass, hormone receptor negativity, and HER2 positivity. We have previously shown that immune infiltrates are positively associated with these high-risk features, suggesting that manipulating the immune microenvironment in high-risk DCIS could potentially alter disease progression. Patients with high-risk DCIS were enrolled in this 3 × 3 phase 1 dose-escalation pilot study of 2, 4, and 8 mg intralesional injections of the PD-1 immune checkpoint inhibitor, pembrolizumab. Study participants received two intralesional injections, three weeks apart, prior to surgery. Tissue from pre-treatment biopsies and post-treatment surgical resections was analyzed using multiplex immunofluorescence (mIF) staining for various immune cell populations. The intralesional injections were easily administered and well-tolerated. mIF analyses demonstrated significant increases in total T cell and CD8+ T cell percentages in most patients after receiving pembrolizumab, even at the 2 mg dose. T cell expansion was confined primarily to the stroma rather than within DCIS-containing ducts. Neither cleaved caspase 3 (CC3) staining, a marker for apoptosis, nor DCIS volume (as measured by MRI) changed significantly following treatment. Intralesional injection of pembrolizumab is safe and feasible in patients with DCIS. Nearly all patients experienced robust total and CD8+ T cell responses. However, we did not observe evidence of cell death or tumor volume decrease by MRI, suggesting that additional strategies may be needed to elicit stronger anti-tumor immunity.
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Affiliation(s)
- Alexa C Glencer
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Jasmine M Wong
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Nola M Hylton
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Gregor Krings
- Department of Pathology, University of California San Francisco, San Francisco, CA, USA
| | - Emma McCune
- University of California San Francisco School of Medicine, San Francisco, CA, USA
| | - Harriet T Rothschild
- University of California San Francisco School of Medicine, San Francisco, CA, USA
| | - Tristan A Loveday
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Michael D Alvarado
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Laura J Esserman
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA
| | - Michael J Campbell
- Department of Surgery, University of California San Francisco, San Francisco, CA, USA.
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42
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Miao KZ, Kim GY, Meara GK, Qin X, Feng H. Tipping the Scales With Zebrafish to Understand Adaptive Tumor Immunity. Front Cell Dev Biol 2021; 9:660969. [PMID: 34095125 PMCID: PMC8173129 DOI: 10.3389/fcell.2021.660969] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2021] [Accepted: 04/19/2021] [Indexed: 12/20/2022] Open
Abstract
The future of improved immunotherapy against cancer depends on an in-depth understanding of the dynamic interactions between the immune system and tumors. Over the past two decades, the zebrafish has served as a valuable model system to provide fresh insights into both the development of the immune system and the etiologies of many different cancers. This well-established foundation of knowledge combined with the imaging and genetic capacities of the zebrafish provides a new frontier in cancer immunology research. In this review, we provide an overview of the development of the zebrafish immune system along with a side-by-side comparison of its human counterpart. We then introduce components of the adaptive immune system with a focus on their roles in the tumor microenvironment (TME) of teleosts. In addition, we summarize zebrafish models developed for the study of cancer and adaptive immunity along with other available tools and technology afforded by this experimental system. Finally, we discuss some recent research conducted using the zebrafish to investigate adaptive immune cell-tumor interactions. Without a doubt, the zebrafish will arise as one of the driving forces to help expand the knowledge of tumor immunity and facilitate the development of improved anti-cancer immunotherapy in the foreseeable future.
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Affiliation(s)
- Kelly Z Miao
- Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States
| | - Grace Y Kim
- Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States
| | - Grace K Meara
- Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States
| | - Xiaodan Qin
- Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States
| | - Hui Feng
- Department of Pharmacology & Experimental Therapeutics, Boston University School of Medicine, Boston, MA, United States.,Department of Medicine, Section of Hematology and Medical Oncology, Boston University School of Medicine, Boston, MA, United States
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43
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Oshi M, Angarita FA, Tokumaru Y, Yan L, Matsuyama R, Endo I, Takabe K. A Novel Three-Gene Score as a Predictive Biomarker for Pathologically Complete Response after Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer. Cancers (Basel) 2021; 13:2401. [PMID: 34065619 PMCID: PMC8156144 DOI: 10.3390/cancers13102401] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 05/14/2021] [Indexed: 12/18/2022] Open
Abstract
Although triple-negative breast cancer (TNBC) typically responds better to neoadjuvant chemotherapy (NAC) compared to the other subtypes, a pathological complete response (pCR) is achieved in less than half of the cases. We established a novel three-gene score using genes based on the E2F target gene set that identified pCR after NAC, which showed robust performance in both training and validation cohorts (total of n = 3862 breast cancer patients). We found that the three-gene score was elevated in TNBC compared to the other subtypes. A high score was associated with Nottingham histological grade 3 in TNBC. Across multiple cohorts, high-score TNBC enriched not only E2F targets but also G2M checkpoint and mitotic spindle, which are all cell proliferation-related gene sets. High-score TNBC was associated with homologous recombination deficiency, high mutation load, and high infiltration of Th1, Th2, and gamma-delta T cells. However, the score did not correlate with drug sensitivity for paclitaxel, 5-fluorouracil, cyclophosphamide, and doxorubicin in TNBC human cell lines. High-score TNBC was significantly associated with a high rate of pCR not only in the training cohort but also in the validation cohorts. High-score TNBC was significantly associated with better survival in patients who received chemotherapy but not in patients who did not receive chemotherapy. The three-gene score is associated with a high mutation rate, immune cell infiltration, and predicts response to NAC in TNBC.
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Affiliation(s)
- Masanori Oshi
- Department of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; (R.M.); (I.E.)
| | - Fernando A. Angarita
- Department of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
| | - Yoshihisa Tokumaru
- Department of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
- Department of Surgical Oncology, Graduate School of Medicine, Gifu University, Gifu 501-1193, Japan
| | - Li Yan
- Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA;
| | - Ryusei Matsuyama
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; (R.M.); (I.E.)
| | - Itaru Endo
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; (R.M.); (I.E.)
| | - Kazuaki Takabe
- Department of Surgical Oncology, Roswell Park Cancer Institute, Elm & Carlton Streets, Buffalo, NY 14263, USA; (M.O.); (F.A.A.); (Y.T.)
- Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan; (R.M.); (I.E.)
- Department of Surgery, University at Buffalo, The State University of New York Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY 14263, USA
- Department of Breast Surgery and Oncology, Tokyo Medical University, Tokyo 113-8654, Japan
- Department of Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata 700-8558, Japan
- Department of Breast Surgery, Fukushima Medical University, Fukushima 960-1295, Japan
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Medulloblastoma recurrence and metastatic spread are independent of colony-stimulating factor 1 receptor signaling and macrophage survival. J Neurooncol 2021; 153:225-237. [PMID: 33963961 DOI: 10.1007/s11060-021-03767-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Accepted: 04/26/2021] [Indexed: 01/01/2023]
Abstract
PURPOSE Tumor infiltration by immunosuppressive myeloid cells or tumor-associated macrophages (TAMs) contributes to tumor progression and metastasis. In contrast to their adult counterparts, higher TAM signatures do not correlate with aggressive tumor behavior in pediatric brain tumors. While prominent TAM infiltrates exist before and after radiation, the degree to which irradiated macrophages and microglia support progression or leptomeningeal metastasis remains unclear. Patients with medulloblastoma often present with distant metastases and tumor recurrence is largely incurable, making them prime candidates for the study of novel approaches to prevent neuroaxis dissemination and recurrence. METHODS Macrophage depletion was achieved using CSF-1 receptor inhibitors (CSF-1Ri), BLZ945 and AFS98, with or without whole brain radiation in a variety of medulloblastoma models, including patient-derived xenografts bearing Group 3 medulloblastoma and a transgenic Sonic Hedgehog (Ptch1+/-, Trp53-/-) medulloblastoma model. RESULTS Effective reduction of microglia, TAM, and spinal cord macrophage with CSF-1Ri resulted in negligible effects on the rate of local and spinal recurrences or survival following radiation. Results were comparable between medulloblastoma subgroups. While notably few tumor-infiltrating lymphocytes (TILs) were detected, average numbers of CD3+ TILs and FoxP3+ Tregs did not differ between groups following treatment and tumor aggressiveness by Ki67 proliferation index was unaltered. CONCLUSION In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.
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45
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Berger Fridman I, Ugolini GS, VanDelinder V, Cohen S, Konry T. High throughput microfluidic system with multiple oxygen levels for the study of hypoxia in tumor spheroids. Biofabrication 2021; 13. [PMID: 33440359 DOI: 10.1088/1758-5090/abdb88] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 01/13/2021] [Indexed: 02/07/2023]
Abstract
Replication of physiological oxygen levels is fundamental for modeling human physiology and pathology inin vitromodels. Environmental oxygen levels, applied in mostin vitromodels, poorly imitate the oxygen conditions cells experiencein vivo, where oxygen levels average ∼5%. Most solid tumors exhibit regions of hypoxic levels, promoting tumor progression and resistance to therapy. Though this phenomenon offers a specific target for cancer therapy, appropriatein vitroplatforms are still lacking. Microfluidic models offer advanced spatio-temporal control of physico-chemical parameters. However, most of the systems described to date control a single oxygen level per chip, thus offering limited experimental throughput. Here, we developed a multi-layer microfluidic device coupling the high throughput generation of 3D tumor spheroids with a linear gradient of five oxygen levels, thus enabling multiple conditions and hundreds of replicates on a single chip. We showed how the applied oxygen gradient affects the generation of reactive oxygen species (ROS) and the cytotoxicity of Doxorubicin and Tirapazamine in breast tumor spheroids. Our results aligned with previous reports of increased ROS production under hypoxia and provide new insights on drug cytotoxicity levels that are closer to previously reportedin vivofindings, demonstrating the predictive potential of our system.
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Affiliation(s)
- Ilana Berger Fridman
- Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, United States of America.,Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and Regenerative Medicine and Stem Cell Center, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel
| | - Giovanni Stefano Ugolini
- Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, United States of America
| | - Virginia VanDelinder
- Center for Integrated Technologies, Sandia National Laboratories, PO Box 5800, Albuquerque, NM 87185-1315, United States of America
| | - Smadar Cohen
- Avram and Stella Goldstein-Goren Department of Biotechnology Engineering and Regenerative Medicine and Stem Cell Center, Ben-Gurion University of the Negev, POB 653, Beer-Sheva 84105, Israel
| | - Tania Konry
- Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Boston, MA 02115, United States of America
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Zhang XM, Chen DG, Li SC, Zhu B, Li ZJ. Embryonic Origin and Subclonal Evolution of Tumor-Associated Macrophages Imply Preventive Care for Cancer. Cells 2021; 10:903. [PMID: 33919979 PMCID: PMC8071014 DOI: 10.3390/cells10040903] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/23/2021] [Accepted: 03/25/2021] [Indexed: 01/16/2023] Open
Abstract
Macrophages are widely distributed in tissues and function in homeostasis. During cancer development, tumor-associated macrophages (TAMs) dominatingly support disease progression and resistance to therapy by promoting tumor proliferation, angiogenesis, metastasis, and immunosuppression, thereby making TAMs a target for tumor immunotherapy. Here, we started with evidence that TAMs are highly plastic and heterogeneous in phenotype and function in response to microenvironmental cues. We pointed out that efforts to tear off the heterogeneous "camouflage" in TAMs conduce to target de facto protumoral TAMs efficiently. In particular, several fate-mapping models suggest that most tissue-resident macrophages (TRMs) are generated from embryonic progenitors, and new paradigms uncover the ontogeny of TAMs. First, TAMs from embryonic modeling of TRMs and circulating monocytes have distinct transcriptional profiling and function, suggesting that the ontogeny of TAMs is responsible for the functional heterogeneity of TAMs, in addition to microenvironmental cues. Second, metabolic remodeling helps determine the mechanism of phenotypic and functional characteristics in TAMs, including metabolic bias from macrophages' ontogeny in macrophages' functional plasticity under physiological and pathological conditions. Both models aim at dissecting the ontogeny-related metabolic regulation in the phenotypic and functional heterogeneity in TAMs. We argue that gleaning from the single-cell transcriptomics on subclonal TAMs' origins may help understand the classification of TAMs' population in subclonal evolution and their distinct roles in tumor development. We envision that TAM-subclone-specific metabolic reprogramming may round-up with future cancer therapies.
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Affiliation(s)
- Xiao-Mei Zhang
- Laboratory of Radiation Biology, Laboratory Medicine Center, Department of Blood Transfusion, The Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China;
| | - De-Gao Chen
- Institute of Cancer, The Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China;
| | - Shengwen Calvin Li
- Neuro-Oncology and Stem Cell Research Laboratory, Center for Neuroscience Research, CHOC Children’s Research Institute, Children’s Hospital of Orange County (CHOC), 1201 West La Veta Ave., Orange, CA 92868, USA
- Department of Neurology, University of California-Irvine School of Medicine, 200 S Manchester Ave., Ste 206, Orange, CA 92868, USA
| | - Bo Zhu
- Institute of Cancer, The Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China;
| | - Zhong-Jun Li
- Laboratory of Radiation Biology, Laboratory Medicine Center, Department of Blood Transfusion, The Second Affiliated Hospital, Army Military Medical University, Chongqing 400037, China;
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Kwan A, Winder N, Atkinson E, Al-Janabi H, Allen RJ, Hughes R, Moamin M, Louie R, Evans D, Hutchinson M, Capper D, Cox K, Handley J, Wilshaw A, Kim T, Tazzyman SJ, Srivastava S, Ottewell P, Vadakekolathu J, Pockley G, Lewis CE, Brown JE, Danson SJ, Conner J, Muthana M. Macrophages Mediate the Antitumor Effects of the Oncolytic Virus HSV1716 in Mammary Tumors. Mol Cancer Ther 2021; 20:589-601. [PMID: 33298589 DOI: 10.1158/1535-7163.mct-20-0748] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 09/25/2020] [Accepted: 12/04/2020] [Indexed: 11/16/2022]
Abstract
Oncolytic viruses (OV) have been shown to activate the antitumor functions of specific immune cells like T cells. Here, we show OV can also reprogram tumor-associated macrophage (TAM) to a less immunosuppressive phenotype. Syngeneic, immunocompetent mouse models of primary breast cancer were established using PyMT-TS1, 4T1, and E0771 cell lines, and a metastatic model of breast cancer was established using the 4T1 cell line. Tumor growth and overall survival was assessed following intravenous administration of the OV, HSV1716 (a modified herpes simplex virus). Infiltration and function of various immune effector cells was assessed by NanoString, flow cytometry of dispersed tumors, and immunofluorescence analysis of tumor sections. HSV1716 administration led to marked tumor shrinkage in primary mammary tumors and a decrease in metastases. This was associated with a significant increase in the recruitment/activation of cytotoxic T cells, a reduction in the presence of regulatory T cells and the reprograming of TAMs towards a pro-inflammatory, less immunosuppressive phenotype. These findings were supported by in vitro data demonstrating that human monocyte-derived macrophages host HSV1716 replication, and that this led to immunogenic macrophage lysis. These events were dependent on macrophage expression of proliferating cell nuclear antigen (PCNA). Finally, the antitumor effect of OV was markedly diminished when TAMs were depleted using clodronate liposomes. Together, our results show that TAMs play an essential role in support of the tumoricidal effect of the OV, HSV1716-they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype.
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Affiliation(s)
- Amy Kwan
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Natalie Winder
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Emer Atkinson
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Haider Al-Janabi
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Richard J Allen
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Russell Hughes
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Mohammed Moamin
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Rikah Louie
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Dhanajay Evans
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Matthew Hutchinson
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Drew Capper
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Katie Cox
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Joshua Handley
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Adam Wilshaw
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Taewoo Kim
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Simon J Tazzyman
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Sanjay Srivastava
- Department of Immunotherapeutics and Biotechnology and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, Texas
| | - Penelope Ottewell
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Jayakumar Vadakekolathu
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
- Centre for Health and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Graham Pockley
- John van Geest Cancer Research Centre, School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
- Centre for Health and Understanding Disease (CHAUD), School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom
| | - Claire E Lewis
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
- Sheffield ECMC, Cancer Clinical Trials Centre, Weston Park Hospital, Sheffield, United Kingdom
| | - Janet E Brown
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
- Sheffield ECMC, Cancer Clinical Trials Centre, Weston Park Hospital, Sheffield, United Kingdom
| | - Sarah J Danson
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom
- Sheffield ECMC, Cancer Clinical Trials Centre, Weston Park Hospital, Sheffield, United Kingdom
| | - Joe Conner
- Virttu Biologics Ltd., BioCity Scotland, Newhouse, United Kingdom
| | - Munitta Muthana
- Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.
- Sheffield ECMC, Cancer Clinical Trials Centre, Weston Park Hospital, Sheffield, United Kingdom
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48
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Abstract
Tumor associated macrophages (TAMs) in breast cancers foster several aspects of tumor progression and metastasis, and represent a biomarker associated with an unfavorable clinical outcome. As new therapeutic agents selectively targeting leukocytes enter the clinic whose mechanism of action involves diminishing macrophage infiltration or presence in tumors, it becomes increasingly important to identify those tumors heavily infiltrated by TAMs, as well as monitoring TAM response to therapy. MR imaging with iron oxide nanoparticles enables noninvasive quantification of TAMs in tumors, and thus, provides an easily accessible ex vivo assessment of TAMs for prognosis and related treatment decisions.
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Affiliation(s)
- Heike Daldrup-Link
- Department of Radiology; Molecular Imaging Program at Stanford; Stanford University; Palo Alto, CA USA
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49
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He D, Wang D, Lu P, Yang N, Xue Z, Zhu X, Zhang P, Fan G. Single-cell RNA sequencing reveals heterogeneous tumor and immune cell populations in early-stage lung adenocarcinomas harboring EGFR mutations. Oncogene 2021; 40:355-368. [PMID: 33144684 PMCID: PMC7808940 DOI: 10.1038/s41388-020-01528-0] [Citation(s) in RCA: 136] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 10/03/2020] [Accepted: 10/15/2020] [Indexed: 12/12/2022]
Abstract
Lung adenocarcinoma (LUAD) harboring EGFR mutations prevails in Asian population. However, the inter-patient and intra-tumor heterogeneity has not been addressed at single-cell resolution. Here we performed single-cell RNA sequencing (scRNA-seq) of total 125,674 cells from seven stage-I/II LUAD samples harboring EGFR mutations and five tumor-adjacent lung tissues. We identified diverse cell types within the tumor microenvironment (TME) in which myeloid cells and T cells were the most abundant stromal cell types in tumors and adjacent lung tissues. Within tumors, accompanied by an increase in CD1C+ dendritic cells, the tumor-associated macrophages (TAMs) showed pro-tumoral functions without signature gene expression of defined M1 or M2 polarization. Tumor-infiltrating T cells mainly displayed exhausted and regulatory T-cell features. The adenocarcinoma cells can be categorized into different subtypes based on their gene expression signatures in distinct pathways such as hypoxia, glycolysis, cell metabolism, translation initiation, cell cycle, and antigen presentation. By performing pseudotime trajectory, we found that ELF3 was among the most upregulated genes in more advanced tumor cells. In response to secretion of inflammatory cytokines (e.g., IL1B) from immune infiltrates, ELF3 in tumor cells was upregulated to trigger the activation of PI3K/Akt/NF-κB pathway and elevated expression of proliferation and anti-apoptosis genes such as BCL2L1 and CCND1. Taken together, our study revealed substantial heterogeneity within early-stage LUAD harboring EGFR mutations, implicating complex interactions among tumor cells, stromal cells and immune infiltrates in the TME.
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Affiliation(s)
- Di He
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China
- Shanghai Pulmonary Hospital, Department of Thoracic Surgery, School of Life Sciences and Technology, Tongji University, Shanghai, 200433, China
| | - Di Wang
- Shanghai Pulmonary Hospital, Department of Thoracic Surgery, School of Life Sciences and Technology, Tongji University, Shanghai, 200433, China
| | - Ping Lu
- Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, 200065, China
| | - Nan Yang
- PharmaLegacy Laboratories (Shanghai) Co, Zhangjiang High-Tech Park Ltd, Building 7, 388 Jialilue Road, Shanghai, 201203, China
| | - Zhigang Xue
- Translational Center for Stem Cell Research, Tongji Hospital, Department of Regenerative Medicine, Tongji University School of Medicine, Shanghai, 200065, China
| | - Xianmin Zhu
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
- Shanghai Pulmonary Hospital, Department of Thoracic Surgery, School of Life Sciences and Technology, Tongji University, Shanghai, 200433, China.
| | - Peng Zhang
- Shanghai Pulmonary Hospital, Department of Thoracic Surgery, School of Life Sciences and Technology, Tongji University, Shanghai, 200433, China.
| | - Guoping Fan
- Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China.
- Department of Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA.
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50
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Carbó JM, León TE, Font-Díaz J, De la Rosa JV, Castrillo A, Picard FR, Staudenraus D, Huber M, Cedó L, Escolà-Gil JC, Campos L, Bakiri L, Wagner EF, Caelles C, Stratmann T, Van Ginderachter JA, Valledor AF. Pharmacologic Activation of LXR Alters the Expression Profile of Tumor-Associated Macrophages and the Abundance of Regulatory T Cells in the Tumor Microenvironment. Cancer Res 2020; 81:968-985. [PMID: 33361391 DOI: 10.1158/0008-5472.can-19-3360] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 10/29/2020] [Accepted: 12/18/2020] [Indexed: 11/16/2022]
Abstract
Liver X receptors (LXR) are transcription factors from the nuclear receptor family that are activated by oxysterols and synthetic high-affinity agonists. In this study, we assessed the antitumor effects of synthetic LXR agonist TO901317 in a murine model of syngeneic Lewis Lung carcinoma. Treatment with TO901317 inhibited tumor growth in wild-type, but not in LXR-deficient mice, indicating that the antitumor effects of the agonist depends on functional LXR activity in host cells. Pharmacologic activation of the LXR pathway reduced the intratumoral abundance of regulatory T cells (Treg) and the expression of the Treg-attracting chemokine Ccl17 by MHCIIhigh tumor-associated macrophages (TAM). Moreover, gene expression profiling indicated a broad negative impact of the LXR agonist on other mechanisms used by TAM for the maintenance of an immunosuppressive environment. In studies exploring the macrophage response to GM-CSF or IL4, activated LXR repressed IRF4 expression, resulting in subsequent downregulation of IRF4-dependent genes including Ccl17. Taken together, this work reveals the combined actions of the LXR pathway in the control of TAM responses that contribute to the antitumoral effects of pharmacologic LXR activation. Moreover, these data provide new insights for the development of novel therapeutic options for the treatment of cancer. SIGNIFICANCE: This study reveals unrecognized roles of LXR in the transcriptional control of the tumor microenvironment and suggests use of a synthetic LXR agonist as a novel therapeutic strategy to stimulate antitumor activity.
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Affiliation(s)
- José M Carbó
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, Spain.,Leukaemia Stem Cell Group, Josep Carreras Leukemia Research Institute, Badalona, Spain
| | - Theresa E León
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, Spain.,Department of Haematology, UCL Cancer Institute, University College London, London, United Kingdom
| | - Joan Font-Díaz
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, Spain.,Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
| | - Juan Vladimir De la Rosa
- Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Grupo de Investigación Medio Ambiente y Salud (GIMAS, ULPGC), Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain
| | - Antonio Castrillo
- Unidad de Biomedicina (Unidad Asociada al CSIC), Instituto Universitario de Investigaciones Biomédicas y Sanitarias (IUIBS), Grupo de Investigación Medio Ambiente y Salud (GIMAS, ULPGC), Universidad de Las Palmas de Gran Canaria, Las Palmas, Spain.,Instituto de Investigaciones Biomédicas "Alberto Sols" CSIC-Universidad Autónoma de Madrid, Madrid, Spain
| | - Felix R Picard
- Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany
| | - Daniel Staudenraus
- Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany
| | - Magdalena Huber
- Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany
| | - Lídia Cedó
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Hospitalet de Llobregat, Spain
| | - Joan Carles Escolà-Gil
- Institut d'Investigacions Biomèdiques (IIB) Sant Pau, Barcelona, Spain.,CIBER de Diabetes y Enfermedades Metabólicas Asociadas, CIBERDEM, Hospitalet de Llobregat, Spain
| | - Lucía Campos
- Institute for Medical Microbiology and Hospital Hygiene, University of Marburg, Marburg, Germany.,Departments of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Latifa Bakiri
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Erwin F Wagner
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria.,Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - Carme Caelles
- Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain.,Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, Spain
| | - Thomas Stratmann
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, Spain
| | - Jo A Van Ginderachter
- Lab of Cellular and Molecular Immunology, Vrije Universiteit Brussel, Brussels, Belgium.,Lab of Myeloid Cell Immunology, VIB Center for Inflammation Research, Brussels, Belgium
| | - Annabel F Valledor
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, Spain. .,Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
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