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MYB orchestrates T cell exhaustion and response to checkpoint inhibition.

ABSTRACT: CD8⁺ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion^1,2-is maintained by precursors of exhausted T (T_PEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1^- exhausted effector T cells^3-6. Here we show that the long-term proliferative potential, multipotency and repopulation capacity of exhausted T cells during chronic infection are selectively preserved in a small population of transcriptionally distinct CD62L⁺ T_PEX cells. The transcription factor MYB is not only essential for the development of CD62L⁺ T_PEX cells and maintenance of the antiviral CD8⁺ T cell response, but also induces functional exhaustion and thereby prevents lethal immunopathology. Furthermore, the proliferative burst in response to PD-1 checkpoint inhibition originates exclusively from CD62L⁺ T_PEX cells and depends on MYB. Our findings identify CD62L⁺ T_PEX cells as a stem-like population that is central to the maintenance of long-term antiviral immunity and responsiveness to immunotherapy. Moreover, they show that MYB is a transcriptional orchestrator of two fundamental aspects of exhausted T cell responses: the downregulation of effector function and the long-term preservation of self-renewal capacity.

SUBMITTER: Tsui C

PROVIDER: S-EPMC9452299 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature

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MYB orchestrates T cell exhaustion and response to checkpoint inhibition.

Tsui Carlson C Kretschmer Lorenz L Rapelius Svenja S Gabriel Sarah S SS Chisanga David D Knöpper Konrad K Utzschneider Daniel T DT Nüssing Simone S Liao Yang Y Mason Teisha T Torres Santiago Valle SV Wilcox Stephen A SA Kanev Krystian K Jarosch Sebastian S Leube Justin J Nutt Stephen L SL Zehn Dietmar D Parish Ian A IA Kastenmüller Wolfgang W Shi Wei W Buchholz Veit R VR Kallies Axel A

Nature 20220817 7926

CD8+ T cells that respond to chronic viral infections or cancer are characterized by the expression of inhibitory receptors such as programmed cell death protein 1 (PD-1) and by the impaired production of cytokines. This state of restrained functionality-which is referred to as T cell exhaustion1,2-is maintained by precursors of exhausted T (TPEX) cells that express the transcription factor T cell factor 1 (TCF1), self-renew and give rise to TCF1- exha ...[more]

PMID: 35978192

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Project description:Despite the revolutionary impact of immune checkpoint inhibition on cancer therapy, the lack of response in a subset of patients, as well as the emergence of resistance, remain significant challenges. Here we explore the theoretical consequences of the existence of multiple states of immune cell exhaustion on response to checkpoint inhibition therapy. In particular, we consider the emerging understanding that T cells can exist in various states: fully functioning cytotoxic cells, reversibly exhausted cells with minimal cytotoxicity, and terminally exhausted cells. We hypothesize that inflammation augmented by drug activity triggers transitions between these phenotypes, which can lead to non-genetic resistance to checkpoint inhibitors. We introduce a conceptual mathematical model, coupled with a standard 2-compartment pharmacometric (PK) model, that incorporates these mechanisms. Simulations of the model reveal that, within this framework, the emergence of resistance to checkpoint inhibitors can be mitigated through altering the dose and the frequency of administration. Our analysis also reveals that standard PK metrics do not correlate with treatment outcome. However, we do find that levels of inflammation that we assume trigger the transition from the reversibly to terminally exhausted states play a critical role in therapeutic outcome. A simulation of a population that has different values of this transition threshold reveals that while the standard high-dose, low-frequency dosing strategy can be an effective therapeutic design for some, it is likely to fail a significant fraction of the population. Conversely, a metronomic-like strategy that distributes a fixed amount of drug over many doses given close together is predicted to be effective across the entire simulated population, even at a relatively low cumulative drug dose. We also demonstrate that these predictions hold if the transitions between different states of immune cell exhaustion are triggered by prolonged antigen exposure, an alternative mechanism that has been implicated in this process. Our theoretical analyses demonstrate the potential of mitigating resistance to checkpoint inhibitors via dose modulation.

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MYB orchestrates T cell exhaustion and response to checkpoint inhibition.

Publications

MYB orchestrates T cell exhaustion and response to checkpoint inhibition.

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