FcγRIIB expressed on CD8⁺ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer.

ABSTRACT: Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that FcγRIIB, the only inhibitory IgG-Fc receptor, is expressed on a population of highly differentiated effector CD8⁺ T cells in the tumors of mice and humans, raising the possibility that CD8⁺ T cell responses may be directly modulated by checkpoint inhibitor binding to T cell-expressed FcγRIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human FcγRIIB^pos CD8⁺ T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIB^neg CD8⁺ T cells in vitro. Moreover, frequencies of FcγRIIB^pos CD8⁺ T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was FcγRIIB dependent, because conditional genetic deletion of FcγRIIB on tumor-specific CD8⁺ T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of FcγRIIB^pos CD8⁺ T cells was also dependent on an intact Fc region of the checkpoint inhibitor, in that treatment with Fc-devoid anti-PD-1 F(ab) fragments resulted in increased proliferation of FcγRIIB^pos CD8⁺ T cells, without altering the response of FcγRIIB^neg CD8⁺ T cells. Last, the addition of FcγRIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an FcγRIIB-mediated, cell-autonomous mechanism of CD8⁺ T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.

SUBMITTER: Bennion KB 

PROVIDER: S-EPMC11325091 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature