CD39+CD103+CD8+ T cells enhance neoadjuvant chemoimmunotherapy efficacy in head and neck squamous cell carcinoma.

BACKGROUND: Neoadjuvant chemoimmunotherapy (NACI) has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment. However, some patients still do not respond significantly, partly attributed to insufficient anti-tumor specific T-cells. Thus, identifying the underlying causes of impaired antitumor immunity has become an urgent priority to improve efficacy. METHODS: To investigate the link between anti-tumor specific T cells and NACI efficacy in treating HNSCC, we employed multicolor immunohistochemistry (mIHC) and single-cell RNA sequencing (scRNA-seq). To gain deeper insights into the regulatory mechanisms of these T cell populations, we performed cell-cell interaction analysis and spatial analysis. Furthermore, co-culture experiments were carried out to explore the interactions between the cells. RESULTS: Our scRNA-seq results indicated that the population of CD39+CD103+ (double-positive, DP) CD8+ T cells was dramatically increased in the responders of NACI-treated HNSCC patients, while mIHC analysis confirmed the correlation between DP CD8+ T cells density and NACI response. Functional assays demonstrated that DP CD8+ T cells constitute a distinct T cell subset exhibiting enhanced cytotoxic activity. The cell-cell interaction analysis revealed that DP CD8+ T cells were regulated by the CD90+CD138+ cancer-associated fibroblasts (CAFs) subset, which has been characterized as desmoplastic CAFs (dCAFs). In vitro mechanistic experiments suggested that CD90+CD138+ CAF-derived LAMA-4 may reduce the antitumor capacity of DP CD8+ T cells. CONCLUSIONS: Our study highlights the critical role of DP CD8+ T cells in enhancing NACI efficacy. Meanwhile, further research is warranted to explore the effects of targeting CD90+CD138+ CAFs,a thus regulating the function of DP CD8+ T cells.