Soluble c receptor attenuates anti-tumor responses of CD8(+) T cells in T cell immunotherapy

Abstract

Previous studies have shown that soluble common -chain (sc) modulates CD4(+) T cell immunity with antagonistic functions in c cytokine signaling. However, the role of sc 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 sc of their own producing. While sc significantly inhibits cytotoxicity of CD8(+) T cells, blocking sc 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 sc-deficient CD8(+) T cells than that of wild-type or sc-overexpressing CD8(+) T cells. Blocking of IL-2 and IL-15 signaling by sc 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. What's new? Tumors are equipped with various immune evasion mechanisms, including one that enables escape from cytotoxic CD8(+) T cells, a phenomenon suspected of being modulated by cytokine receptor subunit sc. In this study, sc upregulation following T cell receptor stimulation was associated with dampened IL-2 and IL-15 signaling and impaired CD8(+) T cell activity. In vivo, sc deficiency enhanced effector CD8(+) T-cell expansion and potentiated functional effector T cell activity. Adoptive transfer of sc-deficient CD8(+) T cells into tumor-bearing mice improved control over tumor growth. The findings implicate sc as a promising target for improving adoptive T cell immunotherapy strategies for cancer.