Cisplatin-based chemoradiation induces delayed systemic tumor-specific T cells expansion in patients with locally advanced head and neck cancer

Cisplatin-based concurrent chemoradiation (CRT) remains the standard therapy for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), yet recurrence rates remain high. Immune checkpoint inhibitors (ICIs) combined with CRT have not improved patient outcomes so far, emphasizing the need to elucidate CRT’s immunological effects. We performed longitudinal, multidimensional immune profiling of peripheral blood lymphocytes from patients with LA-HNSCC at baseline (BSL), one month (CRT-1M), and three months (CRT-3M) after cisplatin-based CRT. CRT induced a transient decline in tumor-specific T cells at CRT-1M, followed by a robust expansion at CRT-3M. Transcriptomic analyses revealed an early shift from B cell–associated to T cell–mediated immune pathways, sustained over time. Genes involved in T-cell activation, polarization, and exhaustion exhibited a biphasic expression pattern, with a delayed increase at CRT-3M, coinciding with the emergence of a proinflammatory cytokine milieu. In parallel, CRT expanded circulating immunosuppressive populations, suggesting a compensatory regulatory response. Integrated immune analyses identified distinct post-CRT signatures, with delayed tumor-reactive T-cell expansion and elevated proinflammatory cytokines correlating with favorable clinical outcomes. These findings reveal dynamic and temporally coordinated systemic immune remodeling following CRT and highlight a delayed activation phase that may represent an optimal window for ICI-based combination strategies in LA-HNSCC.