Fcmr regulates mononuclear phagocyte control of anti-tumor immunity

Shawn P Kubli; Larsen Vornholz; Gordon Duncan; Wenjing Zhou; Parameswaran Ramachandran; Jerome Fortin; Maureen Cox; SeongJun Han; Robert Nechanitzky; Duygu Nechanitzky; Bryan E Snow; Lisa Jones; Wanda Y Li; Jillian Haight; Andrew Wakeham; Mark R Bray; Tak W Mak

doi:10.1038/s41467-019-10619-w

Fcmr regulates mononuclear phagocyte control of anti-tumor immunity

Nat Commun. 2019 Jun 18;10(1):2678. doi: 10.1038/s41467-019-10619-w.

Authors

Shawn P Kubli^{1

2}, Larsen Vornholz^{1

3}, Gordon Duncan¹, Wenjing Zhou¹, Parameswaran Ramachandran¹, Jerome Fortin¹, Maureen Cox¹, SeongJun Han^{1

3}, Robert Nechanitzky¹, Duygu Nechanitzky¹, Bryan E Snow¹, Lisa Jones¹, Wanda Y Li¹, Jillian Haight¹, Andrew Wakeham¹, Mark R Bray¹, Tak W Mak^{4

5

6

7}

Affiliations

¹ The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada.
² Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.
³ Department of Immunology, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada.
⁴ The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, 610 University Avenue, Toronto, ON, M5G 2M9, Canada. Tak.mak@uhnresearch.ca.
⁵ Department of Medical Biophysics, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada. Tak.mak@uhnresearch.ca.
⁶ Department of Immunology, University of Toronto, 101 College Street, Toronto, ON, M5G 1L7, Canada. Tak.mak@uhnresearch.ca.
⁷ Department of Medicine, University of Hong Kong, Pok Fu Lam, 999077, Hong Kong. Tak.mak@uhnresearch.ca.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antigen Presentation / drug effects
Antigen Presentation / immunology
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Carcinogenesis / drug effects
Carcinogenesis / immunology
Carrier Proteins / antagonists & inhibitors
Carrier Proteins / genetics
Carrier Proteins / immunology
Carrier Proteins / metabolism*
Cell Line, Tumor / transplantation
Cell Movement / drug effects
Cell Movement / immunology
Female
Lymphocyte Activation / immunology
Melanoma, Experimental / drug therapy
Melanoma, Experimental / immunology*
Melanoma, Experimental / mortality
Melanoma, Experimental / pathology
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics
Membrane Proteins / immunology
Membrane Proteins / metabolism*
Mice
Mice, Inbred C57BL
Mice, Knockout
Monocytes / immunology*
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 / immunology*
Skin Neoplasms / mortality
Skin Neoplasms / pathology
Survival Analysis
T-Lymphocytes / immunology
Tumor Microenvironment / immunology

Substances

Carrier Proteins
Fcmr protein, mouse
Membrane Proteins
Pdcd1 protein, mouse
Programmed Cell Death 1 Receptor