A unified atlas of CD8 T cell dysfunctional states in cancer and infection

Abstract

CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across different experimental and clinical settings. By carrying out a unified analysis of over 300 ATAC-seq and RNA-seq experiments from twelve independent studies of CD8 T cell dysfunction in cancer and infection we defined a shared differentiation trajectory towards terminal dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell activation states across models. Experimental dissection of acute and chronic viral infection using scATAC-seq and allele-specific scRNA-seq identified state-specific transcription factors and captured the early emergence of highly similar TCF1+ progenitor-like populations at an early branch point, at which epigenetic features of functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.

CD8+ T Cell Exhaustion in Cancer

“…Discrepancies regarding CD8 + T ex stability in the presence/absence of antigen may be due to the frequency and quality of TCF-1 + stem-like cells at hand. A unified atlas of 12 studies spanning cancer and chronic viral infection has recently revealed that bifurcation of memory commitment from a dysfunctional program occurs early (in less than 7 days following antigen encounter) ( 61 ). With preclinical cancer models, the time of initial antigen encounter is less controlled for compared to viral infection.…”

Divergent clonal differentiation trajectories of T cell exhaustion

“…Next, we focused on the early programming of exhaustion by comparing D8 scATAC-seq phenotypes in Arm and Cl13 infection (Figure S3A). As previously described, memory precursor cells (T mp ) are present at D8 in Arm infection and cluster with an early Tex prog population present at D8 in Cl13 infection that expresses Tox and Tcf7 (herein referred to as precursor exhausted -Tex prec ), but these subsets were relatively infrequent compared to the effector populations in both infection models (1.4% of D8 cells in Arm infection, 3.3% of cells at D8 in Cl13 infection) [14,41]. We first compared the gene expression and chromatin state programs of T mp and Tex prec subsets, which revealed strong exhaustion-and interferon-induced programs in Tex prec , as expected (Figure S3B, S3C and S3D, Table S9).…”

Spatiotemporal co-dependency between macrophages and exhausted CD8+T cells in cancer

“…Recent studies have reported that development of T cell exhaustion during chronic infection and cancer occurs in a multistep fashion, revealing distinct subtypes with unique transcriptional and epigenetic dynamics, as well as their ability to respond to immune checkpoint blockade (Im et al, 2016;Philip et al, 2017;Satpathy et al, 2019;Siddiqui et al, 2019;Jansen et al, 2019;Miller et al, 2019;Beltra et al, 2020;Pritykin et al, 2021).…”