posted on 2024-09-16, 09:44authored byWenfeng 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 has no effect on proliferation, migration and invasion of CRC cells.
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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 (CRC), where KRT17 reversed the tumor immunosuppressive microenvironment by increasing T-lymphocyte infiltration. High-throughput RNA sequencing suggested KRT17 was significantly upregulated in deficient mismatch repair (dMMR) tumors compared to proficient mismatch repair (pMMR) tumors. In a CRC 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 co-immunoprecipitation assays suggested KRT17 caused YTHDF2 degradation through the ubiquitin-proteasome system. Through high-throughput RNA immunoprecipitation sequencing, we found 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 CRC receiving pembrolizumab, high KRT17 expression was found within the tumors of responders. Collectively, we elucidated a critical role of KRT17 in CRC to prevent immune escape. These findings present new insights into potential therapeutic strategies and effective markers of immunotherapy reactivity against pMMR tumors.