Adiponectin Deficiency Enhances Anti-Tumor Immunity of CD8(+) T Cells in Rhabdomyosarcoma Through Inhibiting STAT3 Activation

Restoring the tumor-killing function of CD8(+) T cells in the tumor microenvironment is an important strategy for cancer immunotherapy. Our previous study indicated that adiponectin (APN) deficiency reprogramed tumor-associated macrophages into an M1-like phenotype to inhibit rhabdomyosarcoma growth. However, whether APN can directly regulate the anti-tumor activity of CD8(+) T cells remains unknown. In the present study, our results showed that exogenous APN inhibited in vitro CD8(+) T cell migration as well as cytokines IFN-γ and TNF-α production. APN deficiency in vivo strengthened CD8(+) T cell activation and cytotoxicity to restrain rhabdomyosarcoma, evidenced by an increase in the expression of IFN-γ and perforin in CD8(+) T cells and the frequency of CD8(+)IFN-γ(+) T cells in the spleen and lymph nodes, as well as increasing cytokine production of IFN-γ, perforin, TNF-α, and decreasing cytokine production of IL-10 in the serum. Mechanistically, STAT3 was identified as a target of APN in negatively regulating the anti-tumor activity of CD8(+) T cells. In vivo, a STAT3 inhibitor remarkably increased CD8(+) as well as CD8(+)IFN-γ(+) T cells in the spleen and lymph nodes. Taken together, we substantiated that APN deficiency directly maintains the activation of CD8(+) T cells to inhibit rhabdomyosarcoma growth by suppressing STAT3 activation, indicating a promising APN-based therapy for the treatment of rhabdomyosarcoma.