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

Abstract

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.

Imaging-based adipose biomarkers for predicting clinical outcomes of cancer patients treated with immune checkpoint inhibitors: a systematic review

“…Tumor-infiltrating lymphocytes are also found to increase markers of exhaustion in diet-induced obese (DIO) mice, while progression rates in DIO mice are similar to control mice after anti-PD-L1 therapy ( 62 ). Adiponectin, another well-known adipocyte-secreted cytokine, is proven to negatively regulate the anti-tumor activity in CD8+ T cells through the activation of SATA3 ( 63 ). Resistin, a member of the resistin-like molecule family, was mostly found to influence the tumor itself.…”

“…Adiponectin, another well-known adipocyte-secreted cytokine, is proven to negatively regulate the anti-tumor activity in CD8+ T cells through the activation of SATA3 (63). Resistin, a member of the resistin-like molecule family, was mostly found to influence the tumor itself.…”

Role of Leptin and Adiponectin in Carcinogenesis

“…Furthermore, adiponectin regulates JmJC family histone demethylase 3 (JMJD3), which is necessary for M2 polarization, as another anti-inflammatory mechanism [109]. Adiponectin deficiency plays an important role in restraint tumor growth by reprogramming TAMs into M1 macrophages via suppressing p38 MAPK phosphorylation and partially mediating adiponectin-induced TAM polarization, which consequently limits tumor growth [14,84]. In the other direction, M1 macrophages also affect the action of adiponectin by reducing the expression of AdipoRs [37].…”