Abstract 594: FcγRIIB expressed on activated CD8+ T cells restrains T cell responsiveness to αPD-1 immune checkpoint blockade in melanoma patients

Abstract

Abstract In this study, we show that FcγRIIB on the surface of CD8+ T cells reduces responsiveness to αPD-1 antibody in melanoma patients, and we suggest therapeutic strategies to improve CD8+ T cell response to PD-1 blockade. Immune checkpoint blockade (ICB) such as PD-1 blockade has drastically improved melanoma patient survival, but not all patients respond to ICB. Elevated expression of inhibitory molecules on CD8+ T cells dampens the antitumor T cell response and limits patient response to ICB. We recently showed that the inhibitory receptor FcγRIIB is expressed on effector-like memory CD8+ T cells and functions in a cell-intrinsic manner to temper activated CD8+ T cells in vivo. We found that FcγRIIB+ CD8+ T cells were more proliferative and secreted more pro-inflammatory cytokines than their FcγRIIB- counterparts. FcγRIIB+ CD8+ T cells also expressed elevated levels of exhaustion/activation markers (PD-1, CTLA-4, etc.). As these markers are also the targets of immune checkpoint blockade, we investigated the response of these cells to checkpoint therapy. Interestingly, FcγRIIB+ cells exhibited significantly reduced proliferation to αPD-1 and αCTLA-4 in vitro compared to FcγRIIB- cells (p<0.05). In stage-IV melanoma patients, we observed a decrease in FcγRIIB+ CD8+ T cells (p<0.05) following administration of nivolumab (αPD-1), a finding replicated in mouse models in vivo. Because ICB utilizes IgG antibody, a canonical ligand for FcγRs, we hypothesized that ICB antibodies could bind FcγRIIB on CD8+ T cells and elicit counterproductive negative signaling. In a B16-melanoma mouse model, genetic deletion of FcγRIIB on CD8+ T cells increased CD8+ T-cell infiltration and IFNγ production at the tumor in αPD-1 treated mice (p<0.05). Further, blocking inhibitory signaling through FcγRIIB in αPD-1-treated animals increased the number of Ki67+, TNF+, and IFNγ+ CD8+ T cells at the tumor and delayed tumor growth compared to αPD-1 treatment alone (p<0.05). Thus, we show that FcγRIIB is a novel inhibitory molecule on CD8+ T cells that limits T-cell responsiveness to αPD-1 immunotherapy and that T cell-expressed FcγRIIB should be a consideration in the development of therapeutic antibodies. We also demonstrate the efficacy of blocking FcγRIIB to enhance the CD8+ T-cell response to αPD-1 in mice, illuminating a potential new therapeutic target to improve melanoma patient response to ICB. Citation Format: Kelsey B. Bennion, Marvi Tariq, Kirsten M. Baecher, Chrystal M. Paulos, Ragini Kudchadkar, Michael C. Lowe, Mandy L. Ford. FcγRIIB expressed on activated CD8+ T cells restrains T cell responsiveness to αPD-1 immune checkpoint blockade in melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 594.