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S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3.

ABSTRACT: S1PR1 signaling has been shown to restrain the number and function of regulatory T (Treg) cells in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8(+) T cell recruitment and activation, and promotes tumor growth. T-cell-intrinsic S1PR1 affects Treg cells, but not CD8(+) T cells, as demonstrated by adoptive transfer models and transient pharmacological S1PR1 modulation. An increase in S1PR1 in CD4(+) T cells promotes STAT3 activation and JAK/STAT3-dependent Treg tumor migration, whereas STAT3 ablation in T cells diminishes tumor-associated Treg accumulation and tumor growth. Our study demonstrates a stark contrast between the consequences of S1PR1 signaling in Treg cells in the periphery versus tumors.

SUBMITTER: Priceman SJ

PROVIDER: S-EPMC3988983 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3.

Priceman Saul J SJ Shen Shudan S Wang Lin L Deng Jiehui J Yue Chanyu C Kujawski Maciej M Yu Hua H

Cell reports 20140313 6

S1PR1 signaling has been shown to restrain the number and function of regulatory T (Treg) cells in the periphery under physiological conditions and in colitis models, but its role in regulating tumor-associated T cells is unknown. Here, we show that S1PR1 signaling in T cells drives Treg accumulation in tumors, limits CD8(+) T cell recruitment and activation, and promotes tumor growth. T-cell-intrinsic S1PR1 affects Treg cells, but not CD8(+) T cells, as demonstrated by adoptive transfer models ...[more]

PMID: 24630990

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Project description:Regulatory T cells (Tregs) contribute to an immunosuppressive tumor microenvironment. They play an important role in the establishment and progression of tumors with high Tregs infiltration and present a major obstacle to tumor eradication by immunotherapies. Numerous strategies have been attempted to deplete or block Tregs, although their success has been limited. A CD25-targeted, pyrrolobenzodiazepine (PBD) dimer-based antibody-drug conjugate (ADC) was investigated for its ability to deplete Tregs and induce antitumor immunity. Antitumor activity of CD25-ADC either alone or in combination with an anti-programmed cell death protein 1 (PD-1) antibody was evaluated in CD25-negative syngeneic models that exhibit tumor infiltration of CD25-expressing Tregs, and its pharmacodynamics and pharmacokinetics were assessed. Single low doses of CD25-ADC resulted in potent and durable antitumor activity in established syngeneic solid tumor models and the combination of a suboptimal dose was synergistic with PD-1 blockade. Tumor eradication by the CD25-targeted ADC was CD8+ T cell-dependent and CD25-ADC induced protective immunity. Importantly, while CD25-ADC mediated a significant and sustained intratumoral Tregs depletion, accompanied by a concomitant increase in the number of activated and proliferating tumor-infiltrating CD8+ T effector cells, systemic Tregs depletion was transient, alleviating concerns of potential autoimmune side effects. This study shows that a PBD dimer-based, CD25-targeted ADC is able to deplete Tregs and eradicate established tumors via antitumor immunity. This represents a novel approach to efficiently deplete Tregs via a very potent DNA damaging toxin known to induce immunogenic cell death. Moreover, this study provides proof of concept for a completely new application of ADCs as immunotherapeutic agents, as the main mode of action relies on the ADC directly targeting immune cells, rather than tumor cells. These strong preclinical data warrant the clinical evaluation of camidanlumab tesirine (ADCT-301), a PBD-based ADC targeting human CD25, either alone or in combination with checkpoint inhibitors in solid tumors with known Tregs infiltration. A phase I trial (NCT03621982) of camidanlumab tesirine in patients with selected advanced solid tumors is ongoing.

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S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3.

Publications

S1PR1 is crucial for accumulation of regulatory T cells in tumors via STAT3.

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