| Title: |
FcγRIIB expressed on CD8+ T cells limits responsiveness to PD-1 checkpoint inhibition in cancer. |
| Authors: |
Bennion, Kelsey B., Tariq, Marvi, Wyatt, Megan M., Duneton, Charlotte, Baecher, Kirsten M., Paulos, Chrystal M., Kudchadkar, Ragini R., Lowe, Michael C., Ford, Mandy L. |
| Source: |
Science Translational Medicine; 8/23/2023, Vol. 15 Issue 710, p1-18, 18p |
| Subject Terms: |
T cells, IPILIMUMAB, PROGRAMMED cell death 1 receptors, IMMUNE checkpoint inhibitors, MONOCLONAL antibodies, COLON 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 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. Editor's summary: Although immune checkpoint inhibitors (ICI) has been beneficial for many patients, 40% of patients still fail to respond. To investigate this, Bennion et al. evaluated Fcγ Receptor IIB (FcγRIIB), an inhibitory receptor that has recently been found on activated CD8+ T cells. The authors demonstrated that the Fc portion of the anti–programmed death 1 could bind to FcγRIIB on activated CD8+T cells in mice and reduce efficacy of immunotherapy, which was abrogated by adding an antibody against FcyRIIB to treatment. These results elucidate an unappreciated mechanism of FcγRIIB-mediated, cell-autonomous suppression, suggesting altering the Fc portion of these antibodies could better improve efficacy across patients. —Dorothy Hallberg [ABSTRACT FROM AUTHOR] |
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| Database: |
Complementary Index |
