Immune-checkpoint inhibitors (ICIs) are being tested as neoadjuvant therapies in various solid tumours, including in patients with head and neck squamous cell carcinoma (HNSCC), with promising results. Key findings thus far include that this approach is well-tolerated with favourable clinical outcomes including promising pathological response rates in initial studies. Pathological responses are likely to be increased by combining other agents with anti-PD-(L)1 antibodies. Comparisons of baseline biopsy samples with post-treatment surgical specimens have enabled correlative studies utilizing multiomic and immunogenomic methods. Data from these studies suggest that pretreatment intratumoural tissue-resident memory CD8+ T cells are key drivers of tumour regression and give rise to both local and systemic antitumour immune responses. Analyses of systemic responses have defined a PD-1+KLRG1- circulating CD8+ T cell subpopulation that is highly predictive of response, and revealed the interrelationships between intratumoural clones and circulating CD8+ T cells. Lastly, interrogation of T cell populations within lymph nodes is beginning to delineate the immune crosstalk between the primary tumour and tumour-draining lymph nodes and how this relationship might be disrupted with tumour infiltration of the latter. In this Review, we examine data from trials testing neoadjuvant ICIs in patients with HNSCC, focusing on human papillomavirus-unrelated disease, and highlight correlative immunogenomic findings from these trials.
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