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.
Highlights
Immune cells have both positive and negative effects on tumor progression
Tumor-infiltrating lymphocyte (TIL) densities were similar between genotypes (Supplementary Fig. 1b, c), suggesting that delayed disease progression in Fcmr−/− mice was not due to altered TIL access to the tumor microenvironment (TME)
Fewer regulatory T cells (Treg) were found in tumors of Fcmr−/− mice (Fig. 1b), and the ratio of cytotoxic T lymphocytes (CTL) to Treg was higher in tumors of Fcmr−/− mice than in those of Fcmr+/+ mice (Fig. 1c)
Summary
Immune cells have both positive and negative effects on tumor progression. Often these cell types work to eliminate neoplastic cells, but sometimes they facilitate tumor growth by maintaining the tumor microenvironment (TME)[1,2]. FCMR expression in cell types that have important roles in modulating TME maintenance and anti-tumor immunity, such as monocytes, activated MΦ, and DCs, suggests a potential function for FCMR in myeloid cells function during cancer progression. We were intrigued by the lack of difference in B cell density within B16 tumors in Fcmr+/+ and Fcmr−/− mice (Supplementary Fig. 1c).
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