RT Journal Article SR Electronic T1 Immune Checkpoint Blockade induces peripheral cytotoxicity and persistence of large effector CD8+ T cell clones JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.11.15.383786 DO 10.1101/2020.11.15.383786 A1 RA Watson A1 O Tong A1 R Cooper A1 CA Taylor A1 A Verge de Los Aires A1 EA Mahé A1 I Nassiri A1 MR Middleton A1 BP Fairfax YR 2020 UL http://biorxiv.org/content/early/2020/11/16/2020.11.15.383786.abstract AB Immune checkpoint blockers (ICB) exert their anti-cancer effects via CD8+ T cells, although how responses vary over sub-populations and across clones is incompletely understood. We performed single-cell RNA-sequencing of CD8+ T cells and their receptors pre and post ICB across eight patients, integrating results with bulk-sequencing data (n=169). We identify seven phenotypic subsets with divergent sensitivity to ICB, finding the effector subset demonstrates the most pronounced changes. ICB response was related to clone size, with small and large clones markedly differing in the magnitude and immunological relevance of regulated genes. ICB upregulates mitotic pathways and promotes expansion and survival of larger, more cytotoxic clones. Notably, baseline cytotoxicity, but not correlates of mitosis, associated with progression-free survival; highlighting the importance of the pre-treatment CD8+ immune landscape in long-term response. This work further advances understanding of the molecular determinants of ICB response and assists in the search for peripheral prognostic biomarkers.Competing Interest StatementMRM: reports grants from Roche, grants from Astrazeneca, grants and personal fees from GSK, personal fees and other from Novartis, other from Millenium, personal fees and other from Immunocore, personal fees and other from BMS, personal fees and other from Eisai, other from Pfizer, personal fees, non-financial support and other from Merck/MSD, personal fees and other from Rigontec (acquired by MSD), other from Regeneron, personal fees and other from BiolineRx, personal fees and other from Array Biopharma (now Pfizer), non-financial support and other from Replimune, personal fees from Kineta, personal fees from Silicon Therapeutics, outside the submitted work. BPF: received conference support from BMS.