FcγRIIB is a T cell checkpoint in antitumor immunity
Clara R. Farley, Anna B. Morris, Marvi Tariq, Kelsey B. Bennion, Sayalee Potdar, Ragini Kudchadkar, Michael C. Lowe, Mandy L. Ford
Clara R. Farley, Anna B. Morris, Marvi Tariq, Kelsey B. Bennion, Sayalee Potdar, Ragini Kudchadkar, Michael C. Lowe, Mandy L. Ford
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Research Article Immunology Oncology

FcγRIIB is a T cell checkpoint in antitumor immunity

Abstract

In the setting of cancer, T cells upregulate coinhibitory molecules that attenuate TCR signaling and lead to the loss of proliferative capacity and effector function. Checkpoint inhibitors currently in clinical use have dramatically improved mortality from melanoma yet are not effective in all patients, suggesting that additional pathways may contribute to suppression of tumor-specific CD8+ T cell responses in melanoma. Here, we show that FcγRIIB, an inhibitory Fc receptor previously thought to be exclusively expressed on B cells and innate immune cells, is upregulated on tumor-infiltrating effector CD8+ T cells in an experimental melanoma model and expressed on CD8+ T cells in patients with melanoma. Genetic deficiency of Fcgr2b resulted in enhanced tumor-infiltrating CD8+ T cell responses and significantly reduced tumor burden. Adoptive transfer experiments of Fcgr2b–/– tumor antigen-specific T cells into FcγRIIB-sufficient hosts resulted in an increased frequency of tumor-infiltrating CD8+ T cells with greater effector function. Finally, FcγRIIB was expressed on CD8+ memory T cells isolated from patients with melanoma. These data illuminate a cell-intrinsic role for the FcγRIIB checkpoint in suppressing tumor-infiltrating CD8+ T cells.

Authors

Clara R. Farley, Anna B. Morris, Marvi Tariq, Kelsey B. Bennion, Sayalee Potdar, Ragini Kudchadkar, Michael C. Lowe, Mandy L. Ford

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Figure 4

Specific deletion of FcγRIIB on CD8+ T cells results in increased tumor infiltration and cytokine production during melanoma.

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Specific deletion of FcγRIIB on CD8+ T cells results in increased tumor ...
(A) Experimental design: 106 WT or Fcgr2b–/– OT-I and OT-II cells were adoptively transferred into CD45.1+ mice. One day later, 106 B16-OVA cells were subcutaneously injected into the right flank. The dLN, spleen, and tumor were harvested on days 10 and 14. (B) Gating strategy for analysis of PD-1 and FcγRIIB on OT-I T cells. (C) Representative flow plots of PD-1 and FcγRIIB expression on WT OT-I T cells on days 10 and 14 in the spleen, dLN, and tumor. Frequencies of PD-1– (D) and PD-1+ (E) FcγRIIB+ OT-I CD8+ T cells on days 10 and 14. Representative flow plots (F) and summary data (G) of tumor-infiltrating WT and Fcgr2b–/– OT-I cells on day 14. Representative flow plots (H) and summary data (I) of TNF and IFN-γ+ cells among WT and Fcgr2b–/– OT-I cells in the dLN on day 10. Representative flow plots (J) and summary data (K) of TNF and IFN-γ+ cells among WT and Fcgr2b–/– OT-I cells in the spleen on day 10. Representative flow plots (L) and summary data (M) of IFN-γ+ cells among WT and Fcgr2b–/– OT-I cells in the tumor on day 10. Data shown are representative of 2 independent experiments; n = 3–5 mice/group/experiment. Two-way ANOVA with multiple comparisons was used in D and E. Mann-Whitney U tests were used in G, I, K, and M. (N–P) 106 MACS-purified (>95% CD8+) Thy1.1+ WT or Thy1.1+/Thy1.2+ Fcgr2b–/– OT-I cells and 106 WT OT-II cells were transferred into C57BL/6 mice. One day later, 106 B16-OVA cells were subcutaneously injected. Spleens were harvested on day 14. Representative flow plots (O) of frequencies and (P) absolute numbers of Thy1.1+ WT vs. FcγRIIB–/– Thy1.1+/Thy1.2+ CD8+ CD44hi T cells. Mann-Whitney U test was used in P. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. dLN, draining lymph node.