1. Fcmr regulates mononuclear phagocyte control of anti-tumor immunity.
- Author
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Kubli SP, Vornholz L, Duncan G, Zhou W, Ramachandran P, Fortin J, Cox M, Han S, Nechanitzky R, Nechanitzky D, Snow BE, Jones L, Li WY, Haight J, Wakeham A, Bray MR, and Mak TW
- Subjects
- Animals, Antigen Presentation drug effects, Antigen Presentation immunology, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Carcinogenesis drug effects, Carcinogenesis immunology, Carrier Proteins antagonists & inhibitors, Carrier Proteins genetics, Carrier Proteins immunology, Cell Line, Tumor transplantation, Cell Movement drug effects, Cell Movement immunology, Female, Lymphocyte Activation immunology, Melanoma, Experimental drug therapy, Melanoma, Experimental mortality, Melanoma, Experimental pathology, Membrane Proteins antagonists & inhibitors, Membrane Proteins genetics, Membrane Proteins immunology, Mice, Mice, Inbred C57BL, Mice, Knockout, Monocytes metabolism, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor immunology, Programmed Cell Death 1 Receptor metabolism, Skin Neoplasms drug therapy, Skin Neoplasms mortality, Skin Neoplasms pathology, Survival Analysis, T-Lymphocytes immunology, Tumor Microenvironment immunology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Carrier Proteins metabolism, Melanoma, Experimental immunology, Membrane Proteins metabolism, Monocytes immunology, Skin Neoplasms immunology
- Abstract
Myeloid cells contribute to tumor progression, but how the constellation of receptors they express regulates their functions within the tumor microenvironment (TME) is unclear. We demonstrate that Fcmr (Toso), the putative receptor for soluble IgM, modulates myeloid cell responses to cancer. In a syngeneic melanoma model, Fcmr ablation in myeloid cells suppressed tumor growth and extended mouse survival. Fcmr deficiency increased myeloid cell population density in this malignancy and enhanced anti-tumor immunity. Single-cell RNA sequencing of Fcmr-deficient tumor-associated mononuclear phagocytes revealed a unique subset with enhanced antigen processing/presenting properties. Conversely, Fcmr activity negatively regulated the activation and migratory capacity of myeloid cells in vivo, and T cell activation by bone marrow-derived dendritic cells in vitro. Therapeutic targeting of Fcmr during oncogenesis decreased tumor growth when used as a single agent or in combination with anti-PD-1. Thus, Fcmr regulates myeloid cell activation within the TME and may be a potential therapeutic target.
- Published
- 2019
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