Fc gamma RIIB is a T cell checkpoint in antitumor immunity

• Type of Material: Article
• Authors: Clara R Farley, Emory University; Anna Morris, Emory University; Marvi Tariq, Emory University; Kelsey B Bennion, Emory University; Sayalee Potdar, Emory University; Ragini Kudchadkar, Emory University; Michael Lowe, Emory University; Mandy Ford, Emory University
• Language: English
• Date: 2021-02-22
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2021 Farley et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/jci.insight.135623
• Title of Journal or Parent Work: JCI INSIGHT
• Volume: 6
• Issue: 4
• Grant/Funding Information: This work was supported by NIAID R01 AI073707 (to MLF) and by a Melanoma Innovation Fund Award from the Winship Cancer Institute of Emory University (to MLF). CRF was supported by a Surgical Oncology Melanoma Research Fellowship and Elkin Fellowship Award from the Winship Cancer Institute of Emory University, and ABM was supported by NIH T32 AI070081.
• Keywords: LYMPHOCYTES; IGG; Life Sciences & Biomedicine; Research & Experimental Medicine; B-CELLS; EXPRESSION; COLLAGEN; Medicine, Research & Experimental; METASTATIC MELANOMA; CD19; RECEPTOR IIB; Science & Technology
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Oncology

Abstract

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8+ T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8+ T cells in an experimental melanoma model and expressed on CD8+ T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8+ T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b-/- tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8+ T cells with greater effector function. Finally, FcγRIIB was expressed on CD8+ memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8+ T cells.