Mandy L. Ford

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.