Institute of Blood and Marrow Transplantation, National Clinical Research Center for Hematologic Diseases, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Soochow University, Suzhou, P. R. China.
Immunology Translational Research Programme, Department of Microbiology of Immunology, Yong Loo Lin School of Medicine, Immunology Programme, Life Sciences Institute, National University of Singapore, Singapore, Singapore.
Oncoimmunology. 2022 Jun 15;11(1):2088467. doi: 10.1080/2162402X.2022.2088467. eCollection 2022.
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 . 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 . 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.
白细胞介素-1α（IL-1α）在炎症和造血中发挥重要作用。许多肿瘤表达增加的 IL-1α。然而，分泌的 IL-1α 在肿瘤发展中的免疫调节作用，以及它是否可以作为癌症治疗的靶点尚不清楚。在这里，我们发现肿瘤分泌的 IL-1α 显著促进了肝细胞癌（HCC）的发展。研究发现肿瘤释放的 IL-1α 抑制了 T 和 NK 细胞的激活，以及 CD8 T 细胞的杀伤能力。此外，肿瘤释放的 IL-1α 在脾脏和肿瘤中显著增加了 MDSCs。事实上，较高的肿瘤 IL-1α 表达与 HCC 患者肿瘤中 MDSC 的浸润增加有关。进一步的研究表明，肿瘤释放的 IL-1α 通过 CXCR2 依赖性机制促进 MDSC 向肿瘤微环境的募集。耗尽 MDSCs 可以减少肿瘤释放的 IL-1α 的促肿瘤作用。相反，系统给予重组 IL-1α 蛋白通过激活 T 细胞显著抑制肿瘤的发展。事实上，IL-1α 蛋白可以促进 T 细胞的激活，增强 CD8 T 细胞的细胞毒性。因此，我们的研究表明，肿瘤释放的 IL-1α 通过招募 MDSC 来抑制 T 细胞激活，从而促进肿瘤的发展，而系统给予 IL-1α 蛋白则直接促进抗肿瘤 T 细胞反应。我们进一步确定钙蛋白酶 1 是介导肿瘤 IL-1α 分泌的主要细胞内蛋白酶。钙蛋白酶 1 KO 肿瘤的 IL-1α 释放减少，肿瘤发展减少。因此，我们的发现为分泌的 IL-1α 在肿瘤免疫中的功能及其对免疫治疗的意义提供了新的见解。
