Abstract
Background: The major histocompatibility complex class I (MHC- I) transactivator, nucleotide binding oligomerization domain-like receptor family caspase recruitment domain containing 5 (NLRC5), serves as a target for immune evasion in many cancers, including endometrial cancer (EC). An inhibition of autophagy can contribute to immunotherapy by assisting the MHC-I-mediated antigen presentation in cancer. However, the underlying mechanism for autophagy-regulated MHC-I in EC remains unclear. Our study aimed to investigate the effect of autophagy on NLRC5 and MHC-I-mediated antigen presentation, and to identify the potential mechanisms underlying this process in EC.Methods: We examined the levels of autophagy and MHC-I genes by performing transmission electron microscopy (TEM), RNA-seq sequencing, western blotting, and qRT-PCR. The t-test, F-test, Kaplan-Meier analysis, and Pearson’s correlation analysis were used for statistical evaluations of tissue microarrays. Immunofluorescence staining, co-immunoprecipitation (CO-IP), and glutathione S-transferase (GST) pull-down assay were performed. HEC-1A, AN3CA, and Ishikawa EC cells were transfected designed, and the role of LC3 and NLRC5 in MHC-I-mediated antigen presentation in EC was further evaluated in a xenotransplantation model of HEC-1A cell line. Results: Autophagy was upregulated in EC endometrium as compared to that in normal endometrium. MHC I and NLRC5 expressions were lower in EC endometrium than in normal endometrium. Autophagy played a negative role in the MHC-I genes expression in vitro. Furthermore, a negative correlation was found between LC3 and NLRC5 levels, and LC3 interacted with NLRC5 to inhibit NLRC5-mediated MHC-I antigen presentation pathway in vitro and in vivo. Conclusion: An upregulation of LC3 in EC patients may contribute to tumor immune escape by restricting the NLRC5-mediated MHC-I antigen presentation pathway, suggesting that inhibiting LC3 and promoting NLRC5 may be a promising immunotherapy strategy in the management of EC.