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Yang Luo, Hao Li, Hongsheng Fang, Tingyue Gong, Yongheng Zhao, Wenyan Cao, Minhao Yu, Tingfeng Wang, Haiping Lin, Ming Zhong, ICOS+ CD4+ T cells promote antitumor immunity through Akt/STAT1/T-bet axis in MSS/pMMR colorectal cancer, The Journal of Immunology, 2025;, vkaf040, https://doi.org/10.1093/jimmun/vkaf040
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Abstract
Inducible Co-Stimulator (ICOS), as a T-cell–specific costimulatory receptor that enhances T-cell responses to foreign antigens, plays a crucial role in cancer immunity. However, its role in MSS/pMMR colorectal cancer (CRC) remains unclear. In this study, we demonstrated that ICOS expression decreases as the tumor stages advance and that high ICOS expression is associated with a favorable prognosis in MSS/pMMR CRC. Mechanistically, ICOS promoted the secretion of IFN-γ, TNF-α, and IL-12 in CD4+ T cells through the Akt/STAT1/T-bet axis, leading to the inhibition of MSS/pMMR-CRC-cell proliferation. Importantly, ICOS+ CD4+ T cells enhanced tumor responses to anti-PD-1 therapy in MSS/pMMR CRC. In conclusion, this study revealed that ICOS mediates antitumor immunity by promoting the secretion of cancer-suppressive cytokines. It also suggests that activation of ICOS serves a potential therapeutic strategy for MSS/pMMR CRC.