IL-21 receptor signaling is essential for control of hepatocellular carcinoma growth and immunological memory for tumor challenge

Hepatocellular carcinoma (HCC) is a typical inflammation-associated cancer. IL-21 regulates both innate and adaptive immune responses and has key roles in antitumor and antiviral responses. However, the role of IL-21 in HCC development is poorly defined. In the current study, we explored the role of IL-21R signaling in HCC growth by using IL-21R knockout mice and HCC mouse models. We discovered that IL-21R signaling deficiency promoted HCC growth in tumor-bearing mice. We showed that IL-21R deletion reduced T cells infiltration and activation as well as their function but increased the accumulation of myeloid-derived suppressor cells in tumor tissues to enhance HCC growth. Furthermore, loss of IL-21R signaling in tumor-bearing mice resulted in an imbalance of the systemic immune system characterized by decreased antitumor immune cells and increased immunosuppressive cells in the spleen and lymph nodes. In addition, we revealed that IL-21R signaling is critical for the expansion of antitumor immune cells in the memory immune response to tumor rechallenge. Finally, we showed that the transcriptional levels of IL-21 in the peritumoral region and IL-21R within the tumor are associated with survival and recurrence of HCC patients. In conclusion, our study demonstrates that IL-21R signaling is essential for controlling the development of HCC and immunological memory response to tumor challenge.