Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade
Menée sur 139 patients atteints d'un adénocarcinome primitif du poumon, sur 31 patients atteints d'un cancer avancé du poumon non à petites cellules et 135 patients atteints d'un mélanome avancé, cette étude met en évidence le rôle joué par l'hétérogénéité intratumorale des néo-antigènes dans l'immunité antitumorale et la réponse aux immunothérapies anti PD-1 et anti CTLA-4
As tumors grow they acquire mutations, some of which create neoantigens that influence the response of patients to immune checkpoint inhibitors. We explored the impact of neoantigen intra-tumor heterogeneity (ITH) on anti-tumor immunity. Through integrated analysis of ITH and neoantigen burden, we demonstrate a relationship between clonal neoantigen burden and overall survival in primary lung adenocarcinomas (n = 139). CD8+ tumor-infiltrating lymphocytes reactive to clonal neoantigens were identified in early-stage non-small cell lung cancer (NSCLC) and expressed high levels of PD-1. Sensitivity to PD-1 and CTLA-4 blockade in patients with advanced NSCLC (n = 31) and melanoma (n = 135) was enhanced in tumors enriched for clonal neoantigens. T cells recognizing clonal neoantigens were detectable in patients with durable clinical benefit. Cytotoxic chemotherapy-induced subclonal neoantigens, contributing to an increased mutational load, were enriched in certain poor responders. These data suggest that neoantigen heterogeneity may influence immune surveillance and support therapeutic developments targeting clonal neoantigens.