Fc?RIIB expressed on CD8+ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer

Checkpoint inhibition using Fc-containing monoclonal antibodies has emerged as a powerful therapeutic approach to augment antitumor immunity. We recently showed that Fc?RIIB, 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 Fc?RIIB. Here, we show that despite exhibiting strong proliferative and cytokine responses at baseline, human Fc?RIIBpos CD8(+) T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with Fc?RIIBneg CD8(+) T cells in vitro. Moreover, frequencies of Fc?RIIBpos CD8(+) T cells were reduced after treatment of patients with melanoma with nivolumab in vivo. This reduced responsiveness was Fc?RIIB dependent, because conditional genetic deletion of Fc?RIIB on tumor-specific CD8(+) T cells improved response to checkpoint blockade in B16 and LLC mouse models of cancer. The limited responsiveness of Fc?RIIBpos 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 Fc?RIIBposCD8(+) T cells, without altering the response of Fc?RIIBneg CD8(+) T cells. Last, the addition of Fc?RIIB blockade improved efficacy of PD-1 checkpoint inhibition in mouse models of melanoma, lung, and colon cancer. These results illuminate an Fc?RIIB-mediated, cell-autonomous mechanism of CD8(+) T cell suppression, which limits the efficacy of checkpoint inhibitors during antitumor immune responses in vivo.