Clinical significance of peripheral T-cell repertoire in head and neck squamous cell carcinoma treated with cetuximab and nivolumab

Immunotherapy holds significant promise for treating head and neck squamous cell carcinoma (HNSCC), yet responses are limited to a subset of patients. This research investigates whether analyzing the peripheral T-cell receptor (TCR) repertoire could help identify patients who are more likely to benefit from a combination treatment of cetuximab and nivolumab. We report here updated correlative analysis using all samples profiled with deep immunoSEQ assay to study the peripheral TCR repertoires in peripheral blood mononuclear cells from patients enrolled in a phase I/II trial (NCT03370276). TCR repertoires were analyzed in 67 patients. Of these, 64 had available baseline data. Overall, our findings confirm that a more polyclonal peripheral TCR repertoire is associated with improved response to concurrent cetuximab and nivolumab in HNSCC. While the baseline productive Simpson clonality did not reach statistically significant differences in response groups, significant differences were observed within the HPV-negative subgroup and among patients who had received previous ICI therapy. Additionally, the TCR diversity at baseline and early follow-up was associated with overall survival. TRBV/TRBJ gene usage analysis also identified specific gene pairs associated with patient outcomes. Furthermore, our analysis indicates that the TCR clonality patterns are modulated by prior treatment exposures and tumor HPV status, suggesting a cohort expansion within these subgroups for further validation. Together, this study demonstrates the feasibility of leveraging the peripheral T-cell repertoire profiling and clonality dynamics as predictive biomarkers for immunotherapy efficacy in HNSCC.