Molecular signatures of antitumor neoantigen-reactive T cells from metastatic human cancers
Menée à l'aide d'échantillons tumoraux prélevés sur des patients atteints d'un cancer métastatique, cette étude analyse les profils transcriptomiques des lymphocytes T CD4+ et CD8+ intratumoraux réactifs aux néoantigènes et évalue la performance de signatures moléculaires pour identifier des récepteurs de lymphocytes T capables de reconnaître des antigènes tumoraux
The accurate identification of antitumor T cell receptors (TCRs) represents a major challenge to engineering cell-based cancer immunotherapies. By mapping 55 neoantigen-specific TCR clonotypes (NeoTCRs) from 10 metastatic human tumors to their single-cell transcriptomes, we identified signatures of CD8+ and CD4+ neoantigen-reactive tumor-infiltrating lymphocytes (TIL). Neoantigen-specific TIL exhibited tumor-specific expansion with dysfunctional phenotypes, distinct from blood-emigrant bystanders and regulatory TIL. Prospective prediction and testing of 73 NeoTCR signature-derived clonotypes demonstrated that half the tested TCRs recognized tumor antigens or autologous tumors. NeoTCR signatures identified TCRs targeting driver neoantigens and non-mutated viral/tumor-associated antigens, suggesting a common metastatic TIL exhaustion program. NeoTCR signatures delineate the landscape of TIL across metastatic tumors, enabling successful TCR prediction based purely on TIL transcriptomic states for use in cancer immunotherapy.
Science , résumé, 2021