Title: Development and application of a transcriptional score of human T cell exhaustion

Abstract: T cell exhaustion is a progressive loss of T cell potency in response to excessive antigen stimulation. T cell exhaustion plays an important role in regulatory tolerance and in limiting antitumor immune responses and therapies capable of preventing or reverse exhaustion demonstrate benefit in patients with cancer. Despite the central importance of this phenomena, and the evidence that exhaustion states vary with regard to stage and degree of severity, tools to diagnose exhaustion lack specificity and reliable measures of exhaustion severity have not been developed. In this study, we measured transcriptional signatures in CAR T cells evolving from early to late exhaustion, then created an algorithm to generate the CARTEx score, a quantitative measure of exhaustion severity amenable to application in bulk and single-cell transcriptomic datasets. This scoring procedure enabled us to quantify the severity of T cell exhaustion, evaluate the heterogeneity in CAR and endogenous T cell populations, and study the contributions of exhaustion to drug response and disease. We found that CD8+ T cells displaying high CARTEx scores were associated with cancer therapy non-response and increased COVID-19 disease severity. We also observed increased CARTEx scores in CD8+ T cells from patients’ non-cancer diseases states, including autoimmune psoriasis and STAT3 GOF syndromes.

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