Cancer vaccine overcomes immune evasion of nasopharyngeal carcinoma by restoring MHC-I through transcriptional regulation of NLRC5.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is considered an immune-hot tumour. However, 30-80% of cases exhibit downregulation of antigen processing and presentation machinery (APM), enabling the evasion of host immunosurveillance. While cancer vaccines aim to trigger immune responses against tumour antigens, their efficacy in APM-deficient tumours remains uncertain. This study evaluates the efficacy of cancer vaccine targeting tumour-associated antigens in APM-downregulated NPC cells in vitro and further validates the modulation of APM pathways in vivo. METHODS: APM status was evaluated via differential gene expression analysis of 42 NPC tumours and 4 non-NPC tissues using a 17-gene APM signature. Genes downregulated in NPC and associated with reduced MHC-I expression were identified. MHC-I expression was further examined by immunohistochemistry in 35 tumours and 5 non-NPC tissues. The effect of cancer vaccine on APM gene expression was examined by co-culturing peptide-trained T cells with NPC cells. Next, T cell-mediated cytotoxicity was assessed in an APM-deficient model generated by siRNA-mediated knockdown of NLRC5. Finally, cancer vaccine-induced modulation of APM genes was validated in a poorly immunogenic mouse tumour model. RESULTS: Among the 17-gene APM signature, NLRC5 was the most significantly downregulated gene in NPC and strongly correlated with reduced MHC-I expression. Immunohistochemistry confirmed MHC-I downregulation in 63% of tumours. Co-culture of NPC cells with peptide-trained T cells upregulated NLRC5, and key MHC-I assembly genes (TAP1 and B2M), enhancing MHC-I expression and antigen-specific cytotoxicity in NPC cells expressing the target antigen. Notably, the knockdown of NLRC5 was reversed upon co-culture with peptide-trained T cells, resulting in T cell-mediated cytotoxicity. In vivo, cancer vaccine treatment consistently induced APM gene expression, including NLRC5, supporting its potential in restoring antigen presentation in NPC. CONCLUSIONS: This study demonstrates that peptide-trained T cells can upregulate NLRC5 and MHC-I expressions on tumour cells, thereby restoring antigen presentation and enhancing tumour immunogenicity. These findings underscore the therapeutic potential of cancer vaccines in treating APM-downregulated NPC.