Targeting ALK averts ribonuclease 1-induced immunosuppression and enhances antitumor immunity in hepatocellular carcinoma

• Published in: Nature communications Vol. 15; no. 1; pp. 1009 - 18
• Main Authors: Liu, Chunxiao, Zhou, Chenhao, Xia, Weiya, Zhou, Yifan, Qiu, Yufan, Weng, Jialei, Zhou, Qiang, Chen, Wanyong, Wang, Ying-Nai, Lee, Heng-Huan, Wang, Shao-Chun, Kuang, Ming, Yu, Dihua, Ren, Ning, Hung, Mien-Chie
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.02.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/31; 13/51; 13/95; 631/67/1059; 631/67/580; 692/4028/67/1504/1610/4029; Antibodies; Cancer; Cancer immunotherapy; CD8 antigen; Cytotoxicity; Hepatocellular carcinoma; Humanities and Social Sciences; Immune checkpoint inhibitors; Immunity; Immunosuppression; Immunotherapy; Kinases; Liver cancer; Lymphocytes T; Lymphoma; Macrophages; Microenvironments; Monoclonal antibodies; multidisciplinary; PD-1 protein; Phenotypes; Polarization; Protein-tyrosine kinase; Proteins; Ribonuclease; Science; Science (multidisciplinary); Signal transduction; Tumor microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-45215-0

Tumor-secreted factors contribute to the development of a microenvironment that facilitates the escape of cancer cells from immunotherapy. In this study, we conduct a retrospective comparison of the proteins secreted by hepatocellular carcinoma (HCC) cells in responders and non-responders among a cohort of ten patients who received Nivolumab (anti-PD-1 antibody). Our findings indicate that non-responders have a high abundance of secreted RNase1, which is associated with a poor prognosis in various cancer types. Furthermore, mice implanted with HCC cells that overexpress RNase1 exhibit immunosuppressive tumor microenvironments and diminished response to anti-PD-1 therapy. RNase1 induces the polarization of macrophages towards a tumor growth-promoting phenotype through activation of the anaplastic lymphoma kinase (ALK) signaling pathway. Targeting the RNase1/ALK axis reprograms the macrophage polarization, with increased CD8 + T- and Th1- cell recruitment. Moreover, simultaneous targeting of the checkpoint protein PD-1 unleashes cytotoxic CD8 + T-cell responses. Treatment utilizing both an ALK inhibitor and an anti-PD-1 antibody exhibits enhanced tumor regression and facilitates long-term immunity. Our study elucidates the role of RNase1 in mediating tumor resistance to immunotherapy and reveals an RNase1-mediated immunosuppressive tumor microenvironment, highlighting the potential of targeting RNase1 as a promising strategy for cancer immunotherapy in HCC. Immune checkpoint inhibitors have now been approved for the treatment of advanced hepatocellular carcinoma (HCC), however only a minority of patients appear to benefit. Here the authors report that RNase1 levels predict response to nivolumab (anti-PD1) in patients with HCC and that RNase 1 overexpression correlates with an immunosuppressive tumor microenvironment in HCC preclinical models.