Journal Article

M2-like macrophages dictate clinically relevant immunosuppression in metastatic ovarian cancer

Praznovec, Ivan, Spisek, Radek, Galluzzi, Lorenzo, Pecen, Ladislav, Benes, Vladimir, Vosahlikova, Sarka, Rehackova, Martina, Fucikova, Jitka, Fiser, Karel, Pistolic, Jelena, Drochytek, Vit, Hensler, Michal, Rob, Lukas, Sojka, Ludek, Skapa, Petr, Lanickova, Tereza, Ryska, Ales, Sautes-Fridman, Catherine, Truxova, Iva, Fridman, Wolf Herve, Moserova, Irena, Rakova, Jana, Laco, Jan, Brtnicky, Tomas, Kasikova, Lenka

2020

Overview

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.

• Publisher: BMJ Publishing Group Ltd,BMJ Publishing Group LTD,BMJ Publishing Group
• Subject: Adaptive immunology / Antibodies / Biochemistry, Molecular Biology / Cancer / Chemotherapy / Clinical outcomes / Extracellular matrix / Flow cytometry / Gene expression / Genomics / Gynecology and obstetrics / Human health and pathology / Immunology / Immunotherapy / Immunotherapy Biomarkers / Innate immunity / Life Sciences / macrophages / Medical prognosis / Metastasis / Ovarian cancer / Software / Survival analysis / tumor biomarkers / tumor microenvironment / Variables