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. 2022 Jun 15;11(1):2088467.
doi: 10.1080/2162402X.2022.2088467. eCollection 2022.

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

Dandan Lin  1 , Yu Mei  2 , Lei Lei  1 , Zuhairah Binte Hanafi  1   2 , Ziqi Jin  1 , Yonghao Liu  2 , Yuan Song  2 , Yinsheng Zhang  1 , Bo Hu  1 , Chunliang Liu  1 , Jinhua Lu  2 , Haiyan Liu  2
Affiliations

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

Dandan Lin et al. Oncoimmunology. .

Abstract

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

Keywords: CALPAIN 1; HCC; IL-1α; MDSC.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Tumoral-secreted IL-1α promotes tumor growth in murine HCC models.
Figure 2.
Figure 2.
Tumoral-secreted IL-1α inhibits T and NK cell activation in vivo.
Figure 3.
Figure 3.
Tumoral-secreted IL-1α increases MDSCs in vivo.
Figure 4.
Figure 4.
Systemic administration of recombinant IL-1α inhibits tumor development.
Figure 5.
Figure 5.
Secreted IL-1α promotes T cell activation in vitro.
Figure 6.
Figure 6.
Calpain 1 is essential for tumoral-secreted IL-1α-mediated HCC progression.
Figure 7.
Figure 7.
Calpain 1 KO promoted HCC development in parental hepa1-6 cells.
See this image and copyright information in PMC

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