KRT6A在头颈部鳞状细胞癌中介导免疫排斥和抗PD-1耐药

Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies worldwide and is currently the third leading cause of cancer-related death among Taiwanese men. Immune checkpoint blockade (ICB) therapies, including the PD-1-blocking monoclonal antibodies pembrolizumab and nivolumab, have been approved as first-line and salvage treatments for PD-L1-positive recurrent or metastatic (R/M) HNSCC. However, only a minority of patients derive durable benefit from anti-PD-1 therapy. Both innate and acquired resistance to ICB remain major obstacles to effective treatment. In this study, we investigated potential mechanisms underlying ICB resistance using a syngeneic mouse HNSCC model, MOCL2-1. Serial in vivo and in vitro passaging under anti-PD-1 treatment pressure generated an anti-PD-1-resistant subline, L2-1-R. L2-1-R tumors were immunologically “cold,” characterized by minimal CD8⁺ T-cell infiltration and resistance to anti-PD-1 therapy. RNA sequencing of sequential sublines, along with the anti-PD-1-sensitive subline L2-1-S, revealed distinct transcriptional reprogramming in resistant tumors. KRT6A , a stress-induced keratin, was markedly upregulated in L2-1-R. Knockdown of KRT6A in resistant cells increased CD8⁺ T-cell infiltration and restored responsiveness to anti-PD-1 therapy in vivo. Furthermore, analysis of a clinical cohort of HNSCC patients treated with pembrolizumab demonstrated that high KRT6A expression was associated with poor therapeutic response. Together, these findings identify KRT6A as a key mediator of immune exclusion and resistance to PD-1 blockade in HNSCC, suggesting that targeting KRT6A-related pathways may enhance immunotherapy efficacy.