Soluble γc receptor attenuates anti‐tumor responses of CD8 + T cells in T cell immunotherapy

Previous studies have shown that soluble common γ‐chain (sγc) modulates CD4 + T cell immunity with antagonistic functions in γc cytokine signaling. However, the role of sγc in functional properties of effector CD8 + T cells has not been fully defined. In this study, we report a new mechanism by which the anti‐tumor activity of mouse CD8 + T cells is suppressed in sγc of their own producing. While sγc significantly inhibits cytotoxicity of CD8 + T cells, blocking sγc production by genetic modification leads to potentiated effector function of CD8 + T cells, establishing persistent CD8 + T cells. This is due to the modulation of IL‐2 and IL‐15 signaling, which is required for expansion and survival of CD8 + T cells as well as for optimal cytotoxic activity. More efficient management of tumor growth was achieved by an adoptive transfer of sγc‐deficient CD8 + T cells than that of wild‐type or sγc‐overexpressing CD8 + T cells. Blocking of IL‐2 and IL‐15 signaling by sγc attenuates the capacity of CD8 + T cells to mount an optimal response to the tumor, with both quantitative and qualitative effects on antigen‐specific CD8 + T cells. These results could have a critical implication for the generation and survival of optimal effector T cells for adoptive immunotherapy of cancer.