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.
Highlights
Metastatic melanoma is an aggressive form of skin cancer, with an estimated 91,270 new cases and 9320 disease-related deaths per year [1]
Our data demonstrated a lack of 2.4G2 staining on Fcgr2b–/– CD8+ T cells (Figure 1B), confirming that the staining we observed on WT CD8+ T cells was FcγRIIB and not FcγRIII expression
FcγRIIB was not expressed on WT CD8+ T cells in the Draining lymph node (dLN), spleen, or tumor on day 7; FcγRIIB expression was identified on a subset of CD44hiCD8+ T cells in the dLN, spleen, and tumor on days 10 and 14 (Figure 1, C and D)
Summary
Metastatic melanoma is an aggressive form of skin cancer, with an estimated 91,270 new cases and 9320 disease-related deaths per year [1]. Patients with advanced disease (stages III and IV) have traditionally had a poor prognosis [1], recent advances in the utilization of immune-based therapies have revolutionized the management of metastatic melanoma [2]. Treatment of patients with cancer with mAbs targeting T cell coinhibitory pathways, such as CTLA-4 and PD-1 checkpoint inhibitors, has resulted in enhanced immune function against tumor cells and prolonged survival in patients with metastatic melanoma [4]. Not all patients are responsive to blockade of these specific checkpoint inhibitors, raising the possibility that additional novel checkpoint inhibitors exist and could be therapeutically targeted to further improve survival in patients with melanoma [5]
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