钙蛋白酶 1 调控的肿瘤微环境中 IL-1α 释放的免疫抑制作用

Interleukin-1 (IL-1 ) plays an important role in inflammation and hematopoiesis. Many tumors have increased IL-1 expression.

However, the immune regulatory role of secreted IL-1 in tumor development and whether it can be targeted for cancer therapy are still unclear.

Here, we found that tumoral-secreted IL-1 significantly promoted hepatocellular carcinoma (HCC) development in vivo . Tumoral-released IL-1 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 in both spleens and tumors. Indeed, higher tumoral IL-1 expression is associated with increased tumoral infiltration of MDSCs in HCC patients.

Further studies showed that tumoral-released IL-1 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 . On the contrary, systemic administration of recombinant IL-1 protein significantly inhibited tumor development by activating T cells. In fact, IL-1 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 promoted tumor development through recruiting MDSCs to inhibit T cell activation, while systemic IL-1 directly promoted anti-tumor T cell responses.

We further identified calpain 1 as the major intracellular protease mediating tumoral IL-1 secretion. Calpain 1 KO tumors had diminished IL-1 release and reduced tumor development.

Thus, our findings provide new insights into the functions of secreted IL-1 in tumor immunity and its implications for immunotherapy.