Abstract
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.
Trial registration:
ClinicalTrials.gov NCT03021993.
Keywords:
FLT4/PTEN/PPARG/CDKN2A/YAP1/JAK2; T cell repertoire; T regulatory to Th17 ratio; head-and-neck cancer/oral-cavity SCC; multiplex immunofluorescence; neoadjuvant anti-PD-1/L1 therapy; recurrence-free survival; response, resistance, and recurrence; tumor mutational burden; tumor phylogeny.
© 2021 The Author(s).
Publication types
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Clinical Trial
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents, Immunological / therapeutic use
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / immunology
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Carcinoma, Squamous Cell / surgery
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Cyclin-Dependent Kinase Inhibitor p16 / genetics
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Cyclin-Dependent Kinase Inhibitor p16 / immunology
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Gene Expression Profiling
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Gene Expression Regulation, Neoplastic
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Humans
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Immune Checkpoint Inhibitors / therapeutic use
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Janus Kinase 2 / genetics
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Janus Kinase 2 / immunology
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Mouth Neoplasms / drug therapy*
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Mouth Neoplasms / genetics
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Mouth Neoplasms / immunology
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Mouth Neoplasms / surgery
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Mutation
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Neoadjuvant Therapy / methods
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Neoplasm Recurrence, Local / drug therapy*
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Neoplasm Recurrence, Local / genetics
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Neoplasm Recurrence, Local / immunology
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Neoplasm Recurrence, Local / surgery
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Nivolumab / therapeutic use*
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PTEN Phosphohydrolase / genetics
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PTEN Phosphohydrolase / immunology
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Programmed Cell Death 1 Receptor / antagonists & inhibitors
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Programmed Cell Death 1 Receptor / genetics*
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Programmed Cell Death 1 Receptor / immunology
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / immunology
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Survival Analysis
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T-Lymphocytes, Regulatory / drug effects
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / pathology
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Th17 Cells / drug effects
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Th17 Cells / immunology
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Th17 Cells / pathology
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Treatment Outcome
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Vascular Endothelial Growth Factor Receptor-3 / genetics*
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Vascular Endothelial Growth Factor Receptor-3 / immunology
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YAP-Signaling Proteins / genetics
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YAP-Signaling Proteins / immunology
Substances
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Antineoplastic Agents, Immunological
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CDKN2A protein, human
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Cyclin-Dependent Kinase Inhibitor p16
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Immune Checkpoint Inhibitors
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PDCD1 protein, human
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Programmed Cell Death 1 Receptor
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Receptors, Antigen, T-Cell, alpha-beta
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YAP-Signaling Proteins
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YAP1 protein, human
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Nivolumab
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FLT4 protein, human
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Vascular Endothelial Growth Factor Receptor-3
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JAK2 protein, human
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Janus Kinase 2
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PTEN Phosphohydrolase
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PTEN protein, human
Associated data
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ClinicalTrials.gov/NCT03021993