Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy

Bos, Paula D.; Plitas, George; Rudra, Dipayan; Lee, Sue Y.; Rudensky, Alexander Y.

doi:10.1084/jem.20130762

Cited by 257 publications

(207 citation statements)

References 48 publications

(56 reference statements)

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“…Two other studies showed no effects of aPD-1 therapy on PyMT tumor growth. 20,21 However, in these reports, aCTLA-4 single agent treatment was also shown to be ineffective in controlling tumor growth, unlike our results, which showed 50% clinical benefit. This difference may be due to variations in the treatment regimens and/or the utilization of models of different genetic backgrounds (C57BL/6 mice as opposed to FVB mice used in this study).…”

Section: Discussioncontrasting

confidence: 80%

“…15–18 The MMTV-PyMT model has been used to test CTLA-4 or PD-1 checkpoint inhibition in combination with other therapeutic approaches such as irradiation or inhibition of the tyrosine kinase Axl. 19–21 In these studies, combination approaches provided clinical benefit, whereas single-treatment with checkpoint inhibitors was not efficacious. These data suggest the utility of the PyMT model in discovering synergistic immunotherapeutic drug combinations.…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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The advent of immune checkpoint blockade as a new strategy for immunotherapy has changed the outlook for many aggressive cancers. Although complete tumor eradication is attainable in some cases, durable clinical responses are observed only in a small fraction of patients, underlining urgent need for improvement. We previously showed that RON, a receptor tyrosine kinase expressed in macrophages, suppresses antitumor immune responses, and facilitates progression and metastasis of breast cancer. Here, we investigated the molecular changes that occur downstream of RON activation in macrophages, and whether inhibition of RON can cooperate with checkpoint immunotherapy to eradicate tumors. Activation of RON by its ligand, MSP, altered the gene expression profile of macrophages drastically and upregulated surface levels of CD80 and PD-L1, ligands for T-cell checkpoint receptors CTLA-4 and PD-1. Genetic deletion or pharmacological inhibition of RON in combination with anti-CTLA-4, but not with anti-PD-1, resulted in improved clinical responses against orthotopically transplanted tumors compared to single-agent treatment groups, resulting in complete tumor eradication in 46% of the animals. Positive responses to therapy were associated with higher levels of T-cell activation markers and tumor-infiltrating lymphocytes. Importantly, co-inhibition of RON and anti-CTLA-4 was also effective in clearing metastatic breast cancer cells in lungs, resulting in clinical responses in nearly 60% of the mice. These findings suggest that RON inhibition can be a novel approach to potentiate responses to checkpoint immunotherapy in breast cancer.

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Section: Discussioncontrasting

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

et al. 2018

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“…Our observation that Treg depletion deterred tumor growth resembles those of others. 40,41 Yet, in these studies the efficacy of Treg ablation monotherapy was higher than in ours. This might be related to different mouse models used, which showed a more complete deletion of FoxP3 C Tregs.…”

Section: Discussioncontrasting

confidence: 62%

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

et al. 2014

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C regulatory T cells (Tregs), resulting in defective T cell priming and failure to induce tumor regression. To circumvent these problems we evaluated a novel combinatorial therapeutic strategy. We show that tumor antigen targeting to DC-SIGN in humanized hSIGN mice via glycans or specific antibodies induces superior T cell priming. Next, this targeted therapy was combined with transient Foxp3 C Treg depletion employing hSIGNxDEREG mice. While Treg depletion alone slightly delayed B16-OVA melanoma growth, only the combination therapy instigated long-term tumor regression in a substantial fraction of mice. This novel strategy resulted in optimal generation of antigen-specific activated CD8C T cells which accumulated in regressing tumors. Notably, Treg depletion also allowed the local appearance of effector T cells specific for endogenous B16 antigens. This indicates that antitumor immune responses can be broadened by therapies aimed at controlling Tregs in tumor environments. Thus, transient inhibition of Treg-mediated immune suppression potentiates DC targeted antigen vaccination and tumor-specific immunity.

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“…+ Tregs play a pivotal role in maintenance of immunological tolerance (117) and also produce cytokines, such as RANKL, that promote breast cancer progression and metastasis (118). Th17 cells produce IL-17A and IL-17F, which accelerate CRC progression (discussed above, ref.…”

Section: Foxp3mentioning

confidence: 99%

Immunity, inflammation, and cancer: an eternal fight between good and evil

Shalapour¹,

Karin²

2015

Journal of Clinical Investigation

588

509

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Transient regulatory T cell ablation deters oncogene-driven breast cancer and enhances radiotherapy

Abstract: Transient ablation of regulatory T cells in a murine model of breast carcinogenesis inhibits primary tumor and lung metastatic growth and enhances the therapeutic effect of radiotherapy, but not immune checkpoint blockade.

Cited by 257 publications

References 48 publications

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth

Antigen targeting to dendritic cells combined with transient regulatory T cell inhibition results in long-term tumor regression

Immunity, inflammation, and cancer: an eternal fight between good and evil

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