1. Targeting MARCO and IL37R on Immunosuppressive Macrophages in Lung Cancer Blocks Regulatory T Cells and Supports Cytotoxic Lymphocyte Function.
- Author
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La Fleur L, Botling J, He F, Pelicano C, Zhou C, He C, Palano G, Mezheyeuski A, Micke P, Ravetch JV, Karlsson MCI, and Sarhan D
- Subjects
- A549 Cells, Animals, Carcinoma, Non-Small-Cell Lung genetics, Carcinoma, Non-Small-Cell Lung immunology, Carcinoma, Non-Small-Cell Lung pathology, Carcinoma, Non-Small-Cell Lung therapy, Cells, Cultured, Female, Gene Expression Regulation, Neoplastic, Humans, Immune Tolerance genetics, Immune Tolerance immunology, Immunotherapy methods, Interleukin-1 genetics, Interleukin-1 metabolism, Lung Neoplasms genetics, Lung Neoplasms immunology, Lung Neoplasms pathology, Lung Neoplasms therapy, Lymphocyte Activation genetics, Lymphocyte Activation immunology, Macrophage Activation genetics, Macrophage Activation immunology, Mice, Mice, Knockout, Molecular Targeted Therapy methods, T-Lymphocytes, Regulatory pathology, Tumor Escape immunology, Tumor Microenvironment immunology, Tumor-Associated Macrophages immunology, Receptors, Immunologic antagonists & inhibitors, Receptors, Immunologic genetics, Receptors, Immunologic immunology, Receptors, Interleukin-1 antagonists & inhibitors, Receptors, Interleukin-1 genetics, Receptors, Interleukin-1 immunology, T-Lymphocytes, Cytotoxic immunology, T-Lymphocytes, Regulatory immunology, Tumor-Associated Macrophages metabolism
- 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 of anti-inflammatory tumor-associated macrophages (TAM) is associated with worse clinical outcome and resistance to therapy. Here we investigated the immune landscape of NSCLC in the presence of protumoral TAMs expressing the macrophage receptor with collagenous structure (MARCO). MARCO-expressing TAM numbers correlated with increased occurrence of regulatory T cells and effector T cells and decreased natural killer (NK) cells in these tumors. Furthermore, transcriptomic data from the tumors uncovered a correlation between MARCO expression and the anti-inflammatory cytokine IL37. In vitro studies subsequently showed that lung cancer cells polarized macrophages to express MARCO and gain an immune-suppressive phenotype through the release of IL37. MARCO-expressing TAMs blocked cytotoxic T-cell and NK-cell activation, inhibiting their proliferation, cytokine production, and tumor killing capacity. Mechanistically, MARCO
+ macrophages enhanced regulatory T (Treg) cell proliferation and IL10 production and diminished CD8 T-cell activities. Targeting MARCO or IL37 receptor (IL37R) by antibody or CRISPR knockout of IL37 in lung cancer cell lines repolarized TAMs, resulting in recovered cytolytic activity and antitumoral capacity of NK cells and T cells and downmodulated Treg cell activities. In summary, our data demonstrate a novel immune therapeutic approach targeting human TAMs immune suppression of NK- and T-cell antitumor activities. SIGNIFICANCE: This study defines tumor-derived IL37 and the macrophage scavenger receptor MARCO as potential therapeutic targets to remodel the immune-suppressive microenvironment in patients with lung cancer. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/4/956/F1.large.jpg., (©2020 American Association for Cancer Research.)- Published
- 2021
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