Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma
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ABSTRACT: Summary Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer. Graphical abstract Highlights • FLT4 nsSNVs favor response; CDKN2A nsSNVs favor non-response; high TMB improves RFS• Recurrences select for CN loss in PTEN, JAK2 and/or gain in YAP1, MDM2, PPARG• T cell clones (blood) diversify and preexisting clones (tumors) expand with response• High ratios of TREG/Th17 in pretreatment blood predict innate resistance Liu et al. nominate multi-omic correlates of response, recurrence, and survival in individuals treated with neoadjuvant anti-PD-1 therapy for resectable, locally advanced, oral cavity SCC. Future validation of blood- and tumor-based biomarkers and mechanistic insights have implications for neoadjuvant and adjuvant management of individuals with systemic treatment-naive resectable disease.
SUBMITTER: Liu S
PROVIDER: S-EPMC8561238 | biostudies-literature |
REPOSITORIES: biostudies-literature
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