FcγRIIB expressed on CD8<sup>+</sup>T cells limits responsiveness to PD-1 checkpoint inhibition in cancer
Kelsey B. Bennion, Marvi Tariq, Megan M. Wyatt, Charlotte Duneton, Kirsten Baecher, Chrystal M. Paulos, Ragini R. Kudchadkar, Michael Lowe, Mandy L. Ford
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.