IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy

Su, Ee Wern; Moore, Caitlin J.; Suriano, Samantha; Johnson, Christopher; Songalia, Neizel; Patterson, Alicia; Neitzke, Daniel J.; Andrijauskaite, Kristina; Garrett‐Mayer, Elizabeth; Mehrotra, Shikhar; Paulos, Chrystal M.; Doedens, Andrew L.; Goldrath, Ananda W.; Li, Zihai; Cole, David J.; Rubinstein, Mark P.

doi:10.1126/scitranslmed.aac8155

Cited by 54 publications

(44 citation statements)

References 33 publications

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“…While the conventional signaling functions of the IL2Rγ-chain cytokine receptors are mediated by IL2Rβ, IL2Rγ, and IL7Rα [12], IL15Rα contributes by mediating trans-presentation and both IL2Rα and IL15Rα contribute by increasing the affinity and duration of interactions between IL2Rγ-chain cytokines and their receptors [11–13,29,30]. In assessing the importance of the IL2Rα and IL15Rα subunits in IL-2- and IL-15-mediated proliferation of Th17 cells, we found that monoclonal antibody (PC61) blockade of IL2Rα had minimal effect on IL-2-mediated proliferation (supplementary figure 4b), with IL-2 still stimulating proliferation at significantly lower doses than IL-15.…”

Section: Resultsmentioning

confidence: 99%

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Neitzke

Bowers

Andrijauskaite

et al. 2017

Cancer Immunol Immunother

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Adoptive cellular therapy (ACT) with the Th17 subset of CD4+ T cells can cure established melanoma in preclinical models and holds promise for treating human cancer. However, little is known about the growth factors necessary for optimal engraftment and anti-tumor activity of Th17 cells. Due to the central role of IL-2 receptor gamma chain (IL2Rγ-chain) cytokines (IL-2, IL-7, and IL-15) in the activity and persistence of many T cell subsets after adoptive transfer, we hypothesized that they are important for Th17 cells. We found that Th17 cells proliferated in response to IL-2, IL-7, and IL-15 in vitro. However, in contrast to many other T cell subsets including conventionally activated CD8+ T cells, we found that Th17 cells were resistant to apoptosis in the absence of IL2Rγ-chain cytokines. To determine whether Th17 cells utilize IL2Rγ-chain cytokines in vivo, we tracked Th17 cell engraftment after adoptive transfer with or without cytokine depletion. Depletion of IL-7 and/or IL-2 decreased initial engraftment, while depletion of IL-15 did not. Supplementation of IL-2 increased initial Th17 engraftment. To assess the clinical relevance of these findings, we treated melanoma-bearing mice with Th17 cell adoptive transfer and concurrent cytokine depletion or supplementation. We found that simultaneous depletion of IL-2 and IL-7 decreased therapeutic efficacy, depletion of IL-15 had no effect, and IL-2 supplementation increased therapeutic efficacy. Our results show that Th17 cells are responsive to IL2Rγ-chain cytokines, and provide insight into the application of these cytokines for Th17-based therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Neitzke

Bowers

Andrijauskaite

et al. 2017

Cancer Immunol Immunother

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“…Overall, our study confirmed previous findings that lymphopenia is not a prerequisite for effective ACT (46). Several other approaches to improve ACT outcomes in the absence of irradiation and chemotherapy have been recently explored, including the use of antibodies for specific cell type depletion (46), genetically engineered tumor-specific T cells (47), Toll-like receptor (TLR) ligands (48) and other γ-chain cytokines (46,49). One foreseeable advantage of the regimen proposed in this study is the absence of CD4 + T cell ablation.…”

Section: Discussionmentioning

confidence: 99%

Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion

Nagy

Jensen

et al. 2017

Clinical Cancer Research

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Purpose Adoptive cell transfer (ACT) is a promising immunotherapeutic approach for cancer. Host lymphodepletion is associated with favorable ACT therapy outcomes, but it may cause detrimental effects in humans. We tested the hypothesis that IL-15 administration enhances ACT in the absence of lymphodepletion. We previously showed that bioactive IL-15 in vivo comprises a stable complex of the IL-15 chain with the IL-15 receptor alpha chain (IL-15Rα), termed heterodimeric IL-15 (hetIL-15). Experimental Design We evaluated the effects of the combination regimen ACT+hetIL-15 in the absence of lymphodepletion by transferring melanoma-specific Pmel-1 T cells into B16 melanoma-bearing mice. Results hetIL-15 treatment delayed tumor growth by promoting infiltration and persistence of both adoptively transferred Pmel-1 cells and endogenous CD8+ T cells into the tumor. In contrast, persistence of Pmel-1 cells was severely reduced following irradiation in comparison to mice treated with hetIL-15. Importantly, we found that hetIL-15 treatment led to the preferential enrichment of Pmel-1 cells in B16 tumor sites in an antigen-dependent manner. Upon hetIL-15 administration, tumor-infiltrating Pmel-1 cells showed a “non-exhausted” effector phenotype, characterized by increased IFN-γ secretion, proliferation and cytotoxic potential and low level of PD-1. hetIL-15 treatment also resulted in an improved Pmel-1 to Treg ratio in the tumor. Conclusions hetIL-15 administration improves the outcome of ACT in lymphoreplete hosts, a finding with significant implications for improving cell-based cancer immunotherapy strategies.

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“…It is well documented that CD25 recycling participates in IL-2-mediated signaling (47,48) and that DOCK8 is also involved in cytoskeletal reorganization (49,50). The defect in IL-2 signaling observed in DOCK8-deficient Tregs could in part be due to abnormal CD25 recycling.…”

Section: Discussionmentioning

confidence: 99%

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

Singh¹,

Eken²,

Hagin³

et al. 2017

JCI Insight

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IL-2Rα mediates temporal regulation of IL-2 signaling and enhances immunotherapy

Cited by 54 publications

References 33 publications

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Murine Th17 cells utilize IL-2 receptor gamma chain cytokines but are resistant to cytokine withdrawal-induced apoptosis

Heterodimeric IL15 Treatment Enhances Tumor Infiltration, Persistence, and Effector Functions of Adoptively Transferred Tumor-specific T Cells in the Absence of Lymphodepletion

DOCK8 regulates fitness and function of regulatory T cells through modulation of IL-2 signaling

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