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Supplementary Fig. 1 from KRT17 Promotes T-lymphocyte Infiltration Through the YTHDF2–CXCL10 Axis in Colorectal Cancer

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posted on 2023-07-05, 08:42 authored by Wenfeng Liang, Huashan Liu, Ziwei Zeng, Zhenxing Liang, Hao Xie, Wenxin Li, Li Xiong, Zhihang Liu, Mian Chen, Haiqing Jie, Xiaobin Zheng, Liang Huang, Liang Kang

KRT17 is highly expressed in CRC tissues compared to tumor-adjacent tissue regardless of MMR status.

Funding

National Natural Science Foundation of China (NSFC)

China Postdoctoral Science Foundation

Basic and Applied Basic Research Foundation of Guangdong Province (廣東省基礎與應用基礎研究專項資金)

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ARTICLE ABSTRACT

Poor infiltration of T lymphocytes has been regarded as a crucial mechanism of tumor immune escape. Here, we demonstrate a protective role of KRT17 in colorectal cancer, where KRT17 reversed the tumor immunosuppressive microenvironment by increasing T-lymphocyte infiltration. High-throughput RNA sequencing suggested that KRT17 was significantly upregulated in deficient mismatch repair (dMMR) tumors compared with proficient mismatch repair (pMMR) tumors. In a colorectal cancer cohort of 446 cases, KRT17 expression positively correlated with better clinical outcomes. Krt17 overexpression decreased xenograft tumor growth in immune-competent mice. T-cell depletion in a murine model showed that the presence of T lymphocytes was necessary for Krt17-mediated disruption of tumorigenesis. Mass spectrometry and coimmunoprecipitation assays suggested KRT17 caused YTHDF2 degradation through the ubiquitin-proteasome system. Through high-throughput RNA immunoprecipitation sequencing, we found that CXCL10 was the target gene of the N6-methyladenosine (m6A) “reader” YTHDF2. KRT17 synergized with anti–PD-1 for better tumor control in an immunotherapy-resistant murine model. In a cohort of patients with colorectal cancer receiving pembrolizumab, high KRT17 expression was found within the tumors of responders. Collectively, we elucidated a critical role of KRT17 in colorectal cancer to prevent immune escape. These findings present new insights into potential therapeutic strategies and effective markers of immunotherapy reactivity against pMMR tumors.

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