Systemic neoantigen-specific T cells reveal central determinants of PD-(L)1 blockade efficacy
Ramade, C.; Thebault, N.; Scarlata, C.-M.; Oreper, D.; Lauzeral-Vizcaino, F.; Jhunjhunwala, S.; Cabarrou, B.; Hornburg, M.; Fournier, C.; Salvioni, A.; Michelas, M.; Sarradin, V.; Leonardi, G. C.; Feliu, V.; Maixent, M.; Scandella, L.; He, M. X.; Darwish, M.; Heidersbach, A.; Ross, C.; Xu, H.; Bouquet, F.; Fonseca, C.; Tom Lesluyes, T.; Congy-Jolivet, N.; Gomez-Roca, C.; Martinez, A.; Devaud, C.; Filleron, T.; Delord, J.-P.; Mazieres, J.; Delamarre, L.; Ayyoub, M.
Show abstract
The contribution of neoantigen-specific T cells to PD-(L)1 efficacy has largely been inferred from tumor mutational burden. We functionally profiled circulating T cell responses against 7,038 predicted HLA-I-restricted and 21,453 HLA-II-restricted neopeptides in 27 patients with advanced non-small cell lung cancer treated with anti-PD-(L)1. CD4 responses were frequent and correlated with neoantigen availability but not clinical benefit. In contrast, the magnitude and breadth of neoantigen-specific CD8 T cell responses were associated with clinical benefit, progression-free and overall survival, independently of tumor mutational burden. Patients mounting coordinated CD4 and CD8 responses experienced improved progression-free survival. Tumors from CD8 responders displayed immune signatures indicative of both T cell priming and effector functions. Circulating neoantigen-specific CD8 T cells recognized endogenously processed antigens, trafficked to tumors, and selectively expanded under therapy while retaining CD28, CD226, and CXCR3 expression. These findings identify coordinated, functionally engaged neoantigen-specific T cell responses as central determinants of PD-(L)1 efficacy.
Matching journals
The top 8 journals account for 50% of the predicted probability mass.