Following up on earlier observations of a population of CD8+ T cells expressing the inhibitory FcγRIIB receptor in tumor models, Bennion and Tariq et al. showed that FcγRIIB+ CD8+ T cells were present at a significant proportion in human PBMCs, and had a higher proliferation and cytokine-producing potential than FcγRIIB- counterparts – properties that are reduced in the presence of FcγRIIB-binding ICB antibodies (anti-PD-1 or anti-CTLA-4). Similar properties were observed when tracking tumor antigen-specific T cells in murine models. T cell-specific deletion of Fcgr2b and especially FcγRIIB antibody blockade synergized with PD-1 blockade in multiple tumor models.
Contributed by Ed Fritsch
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 FcγRIIBpos CD8+ T cells exhibited reduced responsiveness to both PD-1 and CTLA-4 checkpoint inhibition as compared with FcγRIIBneg CD8+ T cells in vitro. Moreover, frequencies of FcγRIIBpos 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 FcγRIIBpos 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 FcγRIIBpos CD8+ T cells, without altering the response of FcγRIIBneg 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.
Author Info: (1) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. (2) D
Author Info: (1) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. (2) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. (3) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. (4) Paediatric Nephrology, Robert Debr Hospital, Paris 75019, France. Emory Transplant Center, Emory University School of Medicine, Atlanta, GA 30322, USA. (5) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. (6) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. (7) Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA. (8) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. (9) Department of Surgery, Emory University School of Medicine, Atlanta, GA 30322, USA. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA. Emory Transplant Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
