KIAA1429 impairs anti-tumor immunity via regulation of PD-L1 and CD8+ T cells in colorectal cancer

Colorectal cancer (CRC) manifests immunotherapy resistance. Therefore, research targeting the CRC immunotherapeutic strategies sheds light on the improvement of clinical treatment. KIAA1429 expression, clinical relevance, and immune correlations were analyzed using TCGA, GEPIA 2.0, and TIMER 2.0 databases. KIAA1429 expression and CD8⁺T cells infiltration were assessed by immunohistochemistry (IHC) in clinical specimens. Molecular functions were investigated through PPI network construction, along with KEGG and GO analyses. m6A binding sites of PD-L1 were predicted using SRAMP database. Expression correlations between KIAA1429 and PD-L1 were validated through cBioPortal analysis and experimental verification in CRC tissues/cell lines using IHC, Western Blot, and qRT-PCR. In CRC homozygous tumor-bearing mice, KIAA1429 was knockdown using siRNA, with treated with PD1 antibody. Tumor volume and weight of mice were observed. Flow cytometry and immunofluorescence were used to detect CD8⁺T cells infiltration, while immunohistochemistry was utilized to measure PD-L1 expression. Results: Bioinformatic analysis revealed that KIAA1429 was highly expressed in CRC, associated with poor prognosis and good diagnosis values, which is negatively correlated with CD8⁺T cells infiltration but positively correlated with PD-L1 expression. In vivo and in vitro experiments verified these results. Besides, knockdown of KIAA1429 in CRC cells significantly reduced PD-L1 mRNA and protein expression. Knockdown of KIAA1429 inhibits tumor growth by increasing CD8⁺T cell infiltration, decreasing PD-L1 expression and enhancing the efficacy of anti-PD1 immunotherapy in two mouse models. Conclusions: In summary, m6A methyltransferase KIAA1429 suppressed CRC tumor immunity by upregulating PD-L1 expression and reducing CD8⁺T cells infiltration. Targeting KIAA1429 might improve CRC anti-tumor immunity and enhance the efficacy of CRC immunotherapy.