Immune suppressive function of IL-1α release in the tumor microenvironment regulated by calpain 1

Interleukin-1 alpha (IL-1 alpha) plays an important role in inflammation and hematopoiesis. Many tumors have increased IL-1 alpha expression. However, the immune regulatory role of secreted IL-1 alpha in tumor development and whether it can be targeted for cancer therapy are still unclear. Here, we found that tumoral-secreted IL-1 alpha significantly promoted hepatocellular carcinoma (HCC) development in vivo. Tumoral-released IL-1 alpha were found to inhibit T and NK cell activation, and the killing capacity of CD8(+) T cells. Moreover, MDSCs were dramatically increased by tumoral-released IL-1 alpha in both spleens and tumors. Indeed, higher tumoral IL-1 alpha expression is associated with increased tumoral infiltration of MDSCs in HCC patients. Further studies showed that tumoral-released IL-1 alpha promoted MDSC recruitment to the tumor microenvironment through a CXCR2-dependent mechanism. Depletion of MDSCs could diminish the tumor-promoting effect of tumoral-released IL-1 alpha. On the contrary, systemic administration of recombinant IL-1 alpha protein significantly inhibited tumor development by activating T cells. In fact, IL-1 alpha protein could promote T cell activation and enhance the cytotoxicity of CD8(+) T cells in vitro. Thus, our study demonstrated that tumoral-released IL-1 alpha promoted tumor development through recruiting MDSCs to inhibit T cell activation, while systemic IL-1 alpha directly promoted anti-tumor T cell responses. We further identified calpain 1 as the major intracellular protease mediating tumoral IL-1 alpha secretion. Calpain 1 KO tumors had diminished IL-1 alpha release and reduced tumor development. Thus, our findings provide new insights into the functions of secreted IL-1 alpha in tumor immunity and its implications for immunotherapy.

Automated summary

Tumoral-released IL-1α promotes tumor development by inhibiting T cell activation and recruiting MDSCs, while systemic IL-1α protein inhibits tumor development and activates T cell responses. Additionally, calpain 1 is identified as a major intracellular protease mediating tumoral IL-1α secretion.