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Antibody-mediated blockade of the IL-23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy

ABSTRACT: Regulatory T cells (Treg) can impede anti-tumor immunity and currently represent a major obstacle to effective cancer immunotherapy. Targeting tumor-infiltrating regulatory Treg while sparing systemic Treg represent optimal approaches to this problem. Here, we provide evidence that the interleukin 23 receptor (IL23R) expressed by tumor-infiltrating Treg promotes suppressive activity. Disruption of the IL23R results in increased responsiveness of destabilized Treg to the IL-12 cytokine, production of g-interferon (IFNg) and recruitment of CD8 T cells that inhibit tumor growth. Since the Treg destabilization pathway that is initiated by IL23R blockade is distinct and independent from the destabilization pathway coupled to Glucocorticoid-Induced TNFR-Related protein (GITR) activation, we examined the impact of coordinate induction of the two destabilization pathways on anti-tumor immune responses. Combined GITR and IL23R antibody treatment of mice inoculated with MC38 tumors resulted in robust and synergistic anti-tumor responses. These findings indicate that delineation of independent Treg destabilization pathways may allow improved approaches to the development of combination immunotherapy for cancers.

ORGANISM(S): Mus musculus

PROVIDER: GSE197287 | GEO | 2022/05/02

REPOSITORIES: GEO

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2021-12-20 | GSE189359 | GEO

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High-dimensional single cell analysis of T cells infiltrating human intrahepatic cholangiocarcinoma [RNA-Seq]

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2021-02-10 | GSE162799 | GEO

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Project description:Engineered cytokine-based approaches for immunotherapy of cancer are poised to enter the clinic, with IL-12 being at the forefront. However, little is known about potential mechanisms of resistance to cytokine therapies. We found that orthotopic murine lung tumors were resistant to systemically delivered IL-12 fused to murine serum albumin (MSA, IL12-MSA) due to low IL-12R expression on tumor-reactive CD8+ T cells. IL2-MSA increased binding of IL12-MSA by tumor-reactive CD8+ T cells, and combined administration of IL12-MSA and IL2-MSA led to enhanced tumor-reactive CD8+ T cell effector differentiation, decreased numbers of tumor-infiltrating CD4+ regulatory T (Treg) cells, and increased survival of lung tumor-bearing mice. Predictably, the combination of IL-2 and IL-12 at therapeutic doses led to significant dose-limiting toxicity. Administering IL-12 and IL-2 analogs with preferential binding to cells expressing IL12rb1 and CD25, respectively, led to a significant extension of survival in mice with lung tumors while abrogating dose-limiting toxicity. These findings suggest that IL-12 and IL-2 represent a rational approach to combination cytokine therapy whose dose-limiting toxicity can be overcome with engineered cytokine variants.

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Lung tumor-infiltrating Treg have divergent transcriptional profiles and function linked to checkpoint blockade response [mouse]

2023-09-11 | GSE235602 | GEO

FOXP3+ regulatory T Cell perturbation mediated by the IFNγ-STAT1-IFITM3 feedback loop is essential for anti-tumor immunity

Project description:Targeting tumor-infiltrating Treg cells is an efficient way to evoke an anti-tumor immune response. How Treg cells fragility and stability are regulated remains largely unknown. IFITM3 and STAT1 are interferon-induced genes that play a positive role in the progression of tumors. Here, we showed that IFITM3-deficient Tregs blunted tumor growth by strengthening the tumor-killing response and displayed the Th1-like Treg phenotype with higher secretion of IFNγ. Mechanistically, depletion of IFITM3 enhances the translation and phosphorylation of STAT1. Conversely, the decreased IFITM3 protein and mRNA levels present in STAT1-deficient Treg cells indicate that STAT1 conversely regulates the expression of IFITM3 to form a feedback loop. Blocking the inflammatory cytokine IFNγ or directly depleting STAT1-IFITM3 axis phenocopies the restored suppressive function of TI-Tregs in the tumor model. Overall, our study demonstrates that the perturbation of TI-Tregs through IFNγ-IFITM3-STAT1 feedback is essential for anti-tumor immunity and constitutes a targetable vulnerability of cancer immunotherapy.

2023-11-21 | GSE248223 | GEO

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