期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 19, 期 3, 页码 981-993出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.79852
关键词
Cancer immunotherapy; DNA damage response; cGAS-STING; galectin
Gal-9 acts as an immunosuppressive regulator in the tumor microenvironment, and combination therapy targeting Gal-9 and ATM shows promising potential for cancer immunotherapy. Induction of Gal-9 via the STING/IFN β signaling pathway is an important mechanism mediating tumor immune escape.
Although current cancer immunotherapies that target PD- 1/PD-L1 immune checkpoint to reinvigorate exhausted T cells have achieved impressive clinical outcomes, only a small proportion of patients respond. New therapeutic targets are therefore needed to be identified to further unleash the anti-tumor potential of T cells and benefit more patients. Galectin-9 (Gal-9), initially identified as a ligand for TIM-3 to induce T cell death, acts as an immunosuppressive regulator in the tumor microenvironment (TME) but its potential as a therapeutic target remains largely elusive. Here we show that antibody neutralization of Gal-9, in combination with inhibition of Ataxia telangiectasia mutated (ATM), a kinase essential for DNA damage response (DDR), is a promising modality for cancer immunotherapy. Genetic depletion of ATM in tumors markedly potentiated anti-Gal-9 therapy in a syngeneic mouse model. Mechanistically, ATM inhibition greatly upregulated Gal-9 expression and secretion in a variety of human and murine tumor cells via the cGAS-STING-interferon beta (IFN beta) innate immune pathway. Combination of Gal- 9 inhibition with AZD1390, a selective ATM inhibitor currently evaluated in clinical trials, significantly suppressed tumor growth and prolonged survival in multiple syngeneic mouse models, including the poorly-immunogenic LLC lung tumors that do not respond to PD-1/PD-L1 blockade, concomitant with increased T cell infiltration. These results reveal Gal-9 induction via STING/IFN beta signaling as an important mechanism mediating tumor immune escape that could be targeted for cancer immunotherapies, and unveil a novel anti-Gal-9-based combination strategy for cancer immunotherapies in a wide variety of malignancies, including those resistant to PD-1/PD-L1 blockade.
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