KRT17 Promotes T-lymphocyte Infiltration Through the YTHDF2–CXCL10 Axis in Colorectal Cancer

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.

Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model

“…The persistent antigen stimulation or immunosuppressive signals can trigger functional decline or exhaustion in CTLs, with lower cytokine production and co-stimulatory molecule expression, and higher expression of immune checkpoint receptors and immunosuppressive enzymes [ 91 ]. Tumor immune exclusion refers to preventing T cell infiltration in tumors with low CTL abundance, known as “cold tumors” [ 90 , 92 ]. Tumor cells utilize different mechanisms to obstruct T cell infiltration.…”

Galangin modulation of the IL-23/IL-17 axis mitigates ulcerative colitis through attenuation of oxidative/nitrative stress and inflammation

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The relationship of KRAS expression with KRAS status, prognosis, and tumor-infiltrated T lymphocytes in colorectal cancer

“…Regarding the density of CD3+/CD8+ T cells, evaluation was conducted in both the tumor invasive margin (IM) and tumor parenchyma regions. The density in these regions was determined by counting the number of positively staining cells per tumor sample 18 ( Figure 3 ).…”