Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
A partir d'échantillons tumoraux prélevés sur 34 patients atteints d'un cancer du poumon non à petites cellules traité à l'aide de pembrolizumab (un anticorps anti PD-1), cette étude met en évidence un ensemble de mutations associées à la réponse thérapeutique
Immune checkpoint inhibitors, which unleash a patient’s own T cells to kill tumors, are revolutionizing cancer treatment. To unravel the genomic determinants of response to this therapy, we used whole-exome sequencing of non–small cell lung cancers treated with pembrolizumab, an antibody targeting programmed cell death-1 (PD-1). In two independent cohorts, higher nonsynonymous mutation burden in tumors associated with improved objective response, durable clinical benefit, and progression-free survival. Efficacy also correlated with the molecular smoking signature, higher neoantigen burden, and DNA repair pathway mutations; each factor was also associated with mutation burden. In one responder, neoantigen-specific CD8+ T cell responses paralleled tumor regression, suggesting that anti-PD-1 therapy enhances neoantigen-specific T cell reactivity. Our results suggest that the genomic landscape of lung cancers shape response to anti-PD-1 therapy.