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

Abstract

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.

Keywords: IL-15; IL-2; adoptive T cell transfer; cancer immunotherapy; cytokine; soluble common gamma chain receptor.