Luo Yang, Li Hao, Fang Hongsheng, Gong Tingyue, Zhao Yongheng, Cao Wenyan, Yu Minhao, Wang Tingfeng, Lin Haiping, Zhong Ming
Department of Gastrointestinal Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
J Immunol. 2025 Jun 1;214(6):1422-1433. doi: 10.1093/jimmun/vkaf040.
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.
诱导性共刺激分子（ICOS）作为一种增强T细胞对外源抗原反应的T细胞特异性共刺激受体，在癌症免疫中发挥着关键作用。然而，其在微卫星稳定/错配修复缺陷型结直肠癌（CRC）中的作用仍不清楚。在本研究中，我们证明ICOS表达随肿瘤分期进展而降低，且高ICOS表达与微卫星稳定/错配修复缺陷型CRC的良好预后相关。机制上，ICOS通过Akt/STAT1/T-bet轴促进CD4+ T细胞中IFN-γ、TNF-α和IL-12的分泌，导致微卫星稳定/错配修复缺陷型CRC细胞增殖受到抑制。重要的是，ICOS+ CD4+ T细胞增强了微卫星稳定/错配修复缺陷型CRC对抗PD-1治疗的肿瘤反应。总之，本研究揭示ICOS通过促进抑癌细胞因子的分泌介导抗肿瘤免疫。这也表明激活ICOS是微卫星稳定/错配修复缺陷型CRC的一种潜在治疗策略。
