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

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.

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.

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.

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.