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KRT17 promotes T-lymphocyte infiltration through the YTHDF2-CXCL10 axis in colorectal cancer.

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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… Click to show full 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.

Keywords: infiltration; krt17; colorectal cancer; tumor; lymphocyte infiltration

Journal Title: Cancer immunology research
Year Published: 2023

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