Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function

Abstract The progression and metastatic capacity of solid tumors are strongly influenced by immune cells in the tumor microenvironment. In non–small cell lung cancer (NSCLC), accumulation anti-inflammatory tumor-associated macrophages (TAM) is associated with worse clinical outcome resistance to therapy. Here we investigated landscape NSCLC presence protumoral TAMs expressing macrophage receptor collagenous structure (MARCO). MARCO-expressing TAM numbers correlated increased occurrence regulatory T effector decreased natural killer (NK) these tumors. Furthermore, transcriptomic data from uncovered a correlation between MARCO expression cytokine IL37. vitro studies subsequently showed that polarized express gain an immune-suppressive phenotype through release blocked cytotoxic T-cell NK-cell activation, inhibiting their proliferation, production, killing capacity. Mechanistically, MARCO+ enhanced (Treg) proliferation IL10 production diminished CD8 activities. Targeting or IL37 (IL37R) antibody CRISPR knockout lines repolarized TAMs, resulting recovered cytolytic activity antitumoral NK downmodulated Treg summary, our demonstrate novel therapeutic approach targeting human suppression NK- antitumor Significance: This study defines tumor-derived scavenger as potential targets remodel microenvironment patients cancer.