1. M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer
- Author
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Vit Drochytek, Ladislav Pecen, Ludek Sojka, Sarka Vosahlikova, Tomas Brtnicky, Michal Hensler, Tereza Lanickova, Jelena Pistolic, Jan Laco, Lorenzo Galluzzi, Vladimir Benes, Jana Rakova, Iva Truxova, Lenka Kasikova, Radek Spisek, Wolf Hervé Fridman, Ales Ryska, Ivan Praznovec, Jitka Fucikova, Irena Moserova, Karel Fiser, Petr Skapa, Catherine Sautès-Fridman, Martina Rehackova, Lukas Rob, Charles University [Prague] (CU), University Hospital Motol [Prague], Faculty of Medicine in Hradec Kralove [Republique Tchèque], Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Weill Medical College of Cornell University [New York], Sandra and Edward Meyer Cancer Center [New-York], and Yale University School of Medicine
- Subjects
0301 basic medicine ,Cancer Research ,medicine.medical_treatment ,Immunology ,[SDV.CAN]Life Sciences [q-bio]/Cancer ,Biology ,[SDV.MHEP.GEO]Life Sciences [q-bio]/Human health and pathology/Gynecology and obstetrics ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,Flow cytometry ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Immunotherapy Biomarkers ,medicine ,Biomarkers, Tumor ,Tumor Microenvironment ,Immunology and Allergy ,Humans ,Neoplasm Metastasis ,Aged ,Retrospective Studies ,Pharmacology ,CD20 ,Aged, 80 and over ,Immunosuppression Therapy ,Ovarian Neoplasms ,Tumor microenvironment ,medicine.diagnostic_test ,CD68 ,Macrophages ,Middle Aged ,medicine.disease ,Primary tumor ,030104 developmental biology ,Cytokine ,Oncology ,[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology ,030220 oncology & carcinogenesis ,tumor biomarkers ,Cancer research ,biology.protein ,Molecular Medicine ,Female ,sense organs ,CD8 - Abstract
BackgroundThe immunological microenvironment of primary high-grade serous carcinomas (HGSCs) has a major impact on disease outcome. Conversely, little is known on the microenvironment of metastatic HGSCs and its potential influence on patient survival. Here, we explore the clinical relevance of the immunological configuration of HGSC metastases.MethodsRNA sequencing was employed on 24 paired primary tumor microenvironment (P-TME) and metastatic tumor microenvironment (M-TME) chemotherapy-naive HGSC samples. Immunohistochemistry was used to evaluate infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ (lysosomal-associated membrane protein 3) dendritic cells (DCs), NKp46+ (natural killer) cells and CD68+CD163+ M2-like tumor-associated macrophages (TAMs), abundance of PD-1+ (programmed cell death 1), LAG-3+ (lymphocyte-activating gene 3) cells, and PD-L1 (programmed death ligand 1) expression in 80 samples. Flow cytometry was used for functional assessments on freshly resected HGSC samples.Results1468 genes were differentially expressed in the P-TME versus M-TME of HGSCs, the latter displaying signatures of extracellular matrix remodeling and immune infiltration. M-TME infiltration by immune effector cells had little impact on patient survival. Accordingly, M-TME-infiltrating T cells were functionally impaired, but not upon checkpoint activation. Conversely, cytokine signaling in favor of M2-like TAMs activity appeared to underlie inhibited immunity in the M-TME and poor disease outcome.ConclusionsImmunosuppressive M2-like TAM infiltrating metastatic sites limit clinically relevant immune responses against HGSCs.
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- 2020