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Regulatory T Cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis

ABSTRACT: In human patients and in mouse models, immunosuppressive regulatory T cells(Tregs)accumulate in Pancreatic Intraepithelial Neoplasia (PanIN), the precursor lesions to pancreatic cancer. Tregs are considered a potential therapeutic target with the goal to reverse immunosuppression in a number of malignancies, including pancreatic cancer. Here, using a genetically engineered mouse that allows at will depletion of Tregs during pancreatic carcinogenesis, we determined that Treg depletion failed to relieve immunosuppression. Contradicting the current paradigm, depletion of Tregs led to accelerated tumorprogression. We demonstratedthat Treg depletion resultsin changes in the fibroblast population, exemplified by loss of Smooth Muscle Actinexpression and an increase the myeloid recruiting chemokines Ccl3, Ccl6, and Ccl8. Treg depletion further resulted ina compensatoryinflux of suppressive myeloid cells, thereby preventing an anti-tumor immune response. Mechanistically, we show that themyeloid recruitment was driven through the CCR1 axis, with the receptor expressed on tumor associated myeloid cells and several ligands up-regulated in epithelial cells and fibroblasts upon Treg depletion. Finally,blockade of CCR1 signalingcombined with Treg-depletionsuccessfully inhibitedtumorigenesis, uncovering the immune-suppressive myeloid CCR1 axis as a potential therapeutic targetin pancreatic cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE140628 | GEO | 2020/01/13

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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Regulatory T Cell depletion causes compensatory immune suppression and accelerated pancreatic carcinogenesis

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