Ke Chen1, Yun Gu1, Yifan Cao2, Hanji Fang1, Kunpeng Lv1, Xin Liu1, Xudong He1, Jieti Wang3, Chao Lin2, Hao Liu2, Heng Zhang2, Hongyong He2, Jiejie Xu4, He Li5, Ruochen Li6. 1. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. 2. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. 3. Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. 4. Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China. jjxufdu@fudan.edu.cn. 5. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. li.he@zs-hospital.sh.cn. 6. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China. rcli12@fudan.edu.cn.
Abstract
BACKGROUND: T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a crucial immune checkpoint and is considered as an emerging target for cancer treatment. However, the clinical significance and immune-related role of TIM3+ cells in gastric cancer remain unknown. This study aimed to investigate the clinical significance of tumour-infiltrating TIM3+ cells and their association with immune contexture in gastric cancer. METHODS: This study enrolled three cohorts, including 436 tumour tissue microarray specimens and 58 fresh tumour tissues of gastric cancer patients from Zhongshan Hospital, and 330 transcriptional data from The Cancer Genome Atlas. TIM3+ cells and their association with CD8+ T cells were evaluated by immunohistochemistry and flow cytometry analyses. Kaplan-Meier curves, Cox model and interaction test were performed to assess clinical outcomes. RESULTS: Tumour-infiltrating TIM3+ cells' high subgroups experienced poorer overall survival and disease-free survival and predicted inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. TIM3 indicated CD8+ T cell dysfunction, which impeded chemotherapeutic responsiveness. Besides, HAVCR2 messenger RNA expression was associated with specific molecular characteristics. CONCLUSIONS: The abundance of tumour-infiltrating TIM3+ cells could identify an immunoevasive subtype gastric cancer with CD8+ T cell dysfunction, suggesting that TIM3 might serve as a promising target for immunotherapy in gastric cancer.
BACKGROUND: T cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is a crucial immune checkpoint and is considered as an emerging target for cancer treatment. However, the clinical significance and immune-related role of TIM3+ cells in gastric cancer remain unknown. This study aimed to investigate the clinical significance of tumour-infiltrating TIM3+ cells and their association with immune contexture in gastric cancer. METHODS: This study enrolled three cohorts, including 436 tumour tissue microarray specimens and 58 fresh tumour tissues of gastric cancer patients from Zhongshan Hospital, and 330 transcriptional data from The Cancer Genome Atlas. TIM3+ cells and their association with CD8+ T cells were evaluated by immunohistochemistry and flow cytometry analyses. Kaplan-Meier curves, Cox model and interaction test were performed to assess clinical outcomes. RESULTS: Tumour-infiltrating TIM3+ cells' high subgroups experienced poorer overall survival and disease-free survival and predicted inferior therapeutic responsiveness to fluorouracil-based adjuvant chemotherapy. TIM3 indicated CD8+ T cell dysfunction, which impeded chemotherapeutic responsiveness. Besides, HAVCR2 messenger RNA expression was associated with specific molecular characteristics. CONCLUSIONS: The abundance of tumour-infiltrating TIM3+ cells could identify an immunoevasive subtype gastric cancer with CD8+ T cell dysfunction, suggesting that TIM3 might serve as a promising target for immunotherapy in gastric cancer.
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