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Adaptive plasticity of IL-10⁺ and IL-35⁺ T_reg cells cooperatively promotes tumor T cell exhaustion.

ABSTRACT: Regulatory T cells (T_reg cells) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. T_reg cells subvert beneficial anti-tumor immunity by modulating inhibitory receptor expression on tumor-infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms have remained elusive. Here, we found that the cytokines IL-10 and IL-35 (Ebi3-IL-12α heterodimer) were divergently expressed by T_reg cell subpopulations in the tumor microenvironment (TME) and cooperatively promoted intratumoral T cell exhaustion by modulating several inhibitory receptor expression and exhaustion-associated transcriptomic signature of CD8⁺ TILs. While expression of BLIMP1 (encoded by Prdm1) was a common target, IL-10 and IL-35 differentially affected effector T cell versus memory T cell fates, respectively, highlighting their differential, partially overlapping but non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated cooperative roles for T_reg cell-derived IL-10 and IL-35 in promoting BLIMP1-dependent exhaustion of CD8⁺ TILs that limits effective anti-tumor immunity.

SUBMITTER: Sawant DV

PROVIDER: S-EPMC6531353 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Suppressive IL-17A+Foxp3+ and ex-Th17 IL-17AnegFoxp3+ Treg cells are a source of tumour-associated Treg cells.

Project description:Th17 and regulatory T (Treg) cells are integral in maintaining immune homeostasis and Th17-Treg imbalance is associated with inflammatory immunosuppression in cancer. Here we show that Th17 cells are a source of tumour-induced Foxp3+ cells. In addition to natural (n)Treg and induced (i)Treg cells that develop from naive precursors, suppressive IL-17A+Foxp3+ and ex-Th17 Foxp3+ cells are converted from IL-17A+Foxp3neg cells in tumour-bearing mice. Metabolic phenotyping of Foxp3-expressing IL-17A+, ex-Th17 and iTreg cells demonstrates the dissociation between the metabolic fitness and the suppressive function of Foxp3-expressing Treg cell subsets. Although all Foxp3-expressing subsets are immunosuppressive, glycolysis is a prominent metabolic pathway exerted only by IL-17A+Foxp3+ cells. Transcriptome analysis and flow cytometry of IL-17A+Foxp3+ cells indicate that Folr4, GARP, Itgb8, Pglyrp1, Il1rl1, Itgae, TIGIT and ICOS are Th17-to-Treg cell transdifferentiation-associated markers. Tumour-associated Th17-to-Treg cell conversion identified here provides insights for targeting the dynamism of Th17-Treg cells in cancer immunotherapy.

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Adaptive plasticity of IL10+ and IL35+ regulatory T cells cooperatively promote intratumoral T cell exhaustion

Project description:Abstract: Regulatory T cells (Tregs) maintain host self-tolerance but are a major barrier to effective cancer immunotherapy. Tregs subvert beneficial anti-tumor immunity by modulating inhibitory receptor (IR) expression on tumor infiltrating lymphocytes (TILs); however, the underlying mediators and mechanisms remain elusive. Here we show that interleukin-10 (IL10) and interleukin-35 (IL35; a heterodimer of Ebi3 and IL12) are reciprocally expressed by Treg-subpopulations in the tumor microenvironment (TME) and cooperatively promote intratumoral T cell exhaustion. Treg-restricted deletion of either Il10/Ebi3 or dual deletion resulted in delayed tumor growth and significant reduction of transcriptomic exhaustion signature associated with reduced expression of B lymphocyte-induced maturation protein-1 (BLIMP1; Prdm1). While the two cytokines share the BLIMP1 axis to drive multi-IR expression; they differentially impact effector vs. memory fate, highlighting their overlapping and non-redundant regulation of anti-tumor immunity. Our results reveal previously unappreciated adaptive plasticity in inhibitory cytokine expression pattern by Tregs in TME for maximal immunosuppression. Data purpose: to understand the segregated cytokine expression pattern and the preferential generation of single cytokine positive Treg subpopulations, we performed single cell RNASeq (scRNAseq) contrasting Tregs isolated from naïve, unchallenged LNs or day 14 B16 tumor from Foxp3Cre-YFP WT mice

2019-04-02 | GSE126184 | GEO

IL-3 is essential for ICOS-L stabilization on mast cells, and sustains the IL-33-induced RORγt+ Treg generation via enhanced IL-6 induction.

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Cs[Cl3 F10 ]: A Propeller-Shaped [Cl3 F10 ]- Anion in a Peculiar A[5] B[5] Structure Type.

Project description:Reaction of CsF with ClF3 leads to Cs[Cl3 F10 ]. It contains a molecular, propeller-shaped [Cl3 F10 ]- anion with a central μ3 -F atom and three T-shaped ClF3 molecules coordinated to it. This anion represents the first example of a heteropolyhalide anion of higher ClF3 content than [ClF4 ]- and is the first Cl-containing interhalogen species with a μ-bridging F atom. The chemical bonds to the central μ3 -F atom are highly ionic and quite weak as the bond lengths within the coordinating XF3 units (X = Cl, and also calculated for Br, I) are almost unchanged in comparison to free XF3 molecules. Cs[Cl3 F10 ] crystallizes in a very rarely observed A[5] B[5] structure type, where cations and anions are each pseudohexagonally close packed, and reside, each with coordination number five, in the trigonal bipyramidal voids of the other.

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Project description:Regulatory T (Treg) cells accumulate into tumors, hindering the success of cancer immunotherapy. Yet, therapeutic targeting of Treg cells shows limited efficacy or leads to autoimmunity. The molecular mechanisms that guide Treg cell stability in tumors remain elusive. In the present study, we identify a cell-intrinsic role of the alarmin interleukin (IL)-33 in the functional stability of Treg cells. Specifically, IL-33-deficient Treg cells demonstrated attenuated suppressive properties in vivo and facilitated tumor regression in a suppression of tumorigenicity 2 receptor (ST2) (IL-33 receptor)-independent fashion. On activation, Il33-/- Treg cells exhibited epigenetic re-programming with increased chromatin accessibility of the Ifng locus, leading to elevated interferon (IFN)-γ production in a nuclear factor (NF)-κB-T-bet-dependent manner. IFN-γ was essential for Treg cell defective function because its ablation restored Il33-/- Treg cell-suppressive properties. Importantly, genetic ablation of Il33 potentiated the therapeutic effect of immunotherapy. Our findings reveal a new and therapeutically important intrinsic role of IL-33 in Treg cell stability in cancer.

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Effect of interleukin (IL)-35 on IL-17 expression and production by human CD4+ T cells.

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IL-12p35 induces expansion of IL-10 and IL-35-expressing regulatory B cells and ameliorates autoimmune disease.

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Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy.

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| S-EPMC8793114 | biostudies-literature