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High-dimensional single cell analysis reveals an effector Treg molecular program that correlates with lung cancer progression

ABSTRACT: Anti-tumor immune responses are counteracted by CD4+ regulatory T (Treg) cells in the tumor micronenvironment, but the molecular mechanisms responsible for the enhanced suppressive activity of Tregs are poorly defined. High-dimensional single cell profiling of millions of single CD4+ and CD8+ T cells from 53 chemotherapy-na‹ve individuals with lung adenocarcinoma identified the transcription factor IRF4 as constitutively expressed by effector CD4+ Tregs present exclusively in tumors. These IRF4+, but not the quiescent IRF4_ÿTregs expressed a vast array of suppressive molecules, positively correlated with multiple inhibitory and exhausted subpopulations of T cells and were more abundant in rapidly progressing patients. Integration of transcriptomic data and whole genome binding sites of transcription factors further revealed that IRF4, either alone or in combination with its partner BATF, directly controlled a molecular program responsible for Treg hyperproliferation and suppressive functions that included CTLA-4, ICOS, TNFRSF9 (4-1BB) and IL1R2, previously shown to impact survival in lung cancer. Thus, interfering with the IRF4-dependent molecular program may represent a novel immunotherapeutic approach capable to block immunosuppression in the tumor microenvironment without inducing autoimmunity in peripheral tissues.ÿ

ORGANISM(S): Homo sapiens

PROVIDER: GSE128822 | GEO | 2020/03/03

REPOSITORIES: GEO

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Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice

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High-dimensional single cell analysis reveals an effector Treg molecular program that correlates with lung cancer progression

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