Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

Sierra, Rosa A.; Trillo-Tinoco, Jimena; Mohamed, Eslam; Yu, Lolie C.; Achyut, Bhagelu R.; Arbab, Ali S.; Bradford, Jennifer W.; Osborne, Barbara A.; Miele, Lucio; Rodríguez, Paulo C.

doi:10.1158/0008-5472.can-17-0357

Cited by 68 publications

(73 citation statements)

References 49 publications

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“…Notch and NF-κB profiles may contribute to identify patients and tumors likely to respond to immunotherapy and to provide a new alternative approach to nonresponders. Promising therapies implied that Notch modulation (anti-Jagged1/2) combined with novel immune checkpoint blockade therapies ( 108 ).…”

Section: Discussionmentioning

confidence: 99%

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

et al. 2018

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The Notch signaling pathway plays multiple roles in driving T-cell fate decisions, proliferation, and aberrant growth. NF-κB is a cell-context key player interconnected with Notch signaling either in physiological or in pathological conditions. This review focuses on how the multilayered crosstalk between different Notches and NF-κB subunits may converge on Foxp3 gene regulation and orchestrate CD4+ regulatory T (Treg) cell function, particularly in a tumor microenvironment. Notably, Treg cells may play a pivotal role in the inhibition of antitumor immune responses, possibly promoting tumor growth. A future challenge is represented by further dissection of both Notch and NF-κB pathways and consequences of their intersection in tumor-associated Treg biology. This may shed light on the molecular mechanisms regulating Treg cell expansion and migration to peripheral lymphoid organs thought to facilitate tumor development and still to be explored. In so doing, new opportunities for combined and/or more selective therapeutic approaches to improve anticancer immunity may be found.

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Section: Discussionmentioning

confidence: 99%

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

et al. 2018

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“…Secondly, tumor immunogenicity regulated by DDR pathways might be enhanced by NOTCH1 inhibition (22), possibly via the direct binding between NOTCH1 and ataxiatelengiectasia mutated (ATM) (24,25). Thirdly, in immune microenvironment, the NOTCH ligands on myeloid-derived suppressor cells (MDSCs) interact with the NOTCH receptor on tumor cells and thereby improve the CSC capacity (26), which in turn increases the expression of NOTCH ligands on MDSCs (27), constituting a positive feedback eventually resulting in immune tolerance (28). Based on these observations, we hypothesized that NOTCH mutation in NSCLC might predict the clinical benefit from immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Identification of DeleteriousNOTCHMutation as Novel Predictor to Efficacious Immunotherapy in NSCLC

Zhang

Hong

Song

et al. 2020

Clinical Cancer Research

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This study involving 5 cohorts (n=1557) identifies NOTCH mutation, especially deleterious NOTCH mutation (del-NOTCH mut), as novel, frequent determinant of sensitivity to immune checkpoint inhibitor (ICI) in EGFR/ALK WT NSCLC. ICI, compared to chemotherapy, conferred limited benefit in the NOTCH-wild-type patients, but remarkably prolonged PFS and OS in the patients harboring del-NOTCH mut. These results indicate the potential that del-NOTCH mut might impact on the treatment choice (ICI vs. chemotherapy) in advanced EGFR/ALK WT NSCLC. More importantly, del-NOTCH mut downregulates NOTCH signaling and is correlated with better ICI efficacy, which unravels a possibility that the monoclonal antibodies or small chemicals aiming NOTCH members or their ligands might enhance the response to ICI. This inference might lead future research to explore the efficacy of adding NOTCH inhibitor to ICI regimen in NSCLC, for the optimization of ICI treatment in clinical practice.

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“…Recently, the Rodriguez lab in collaboration with the Miele and Osborne labs showed that tumor MDSC, unlike circulating MDSC, upregulate expression of Notch ligand Jagged1, and to a lesser extent, Jagged2. This phenomenon is mediated by NF-κB ( 39 ). Treatment with an anti-Jagged1/2-blocking antibody had remarkable therapeutic activity in several mouse models (3LL lung carcinoma and EG-7, an ovalbumin-expressing form of EL-4 lymphoma), which depended upon enhanced CD8 responses ( 39 ).…”

Section: Notch and Mdscmentioning

confidence: 99%

“…This phenomenon is mediated by NF-κB ( 39 ). Treatment with an anti-Jagged1/2-blocking antibody had remarkable therapeutic activity in several mouse models (3LL lung carcinoma and EG-7, an ovalbumin-expressing form of EL-4 lymphoma), which depended upon enhanced CD8 responses ( 39 ). In EG-7 tumors, anti-Jagged antibodies enhanced the effect of anti-ovalbumin adoptive T-cell therapy (ACT).…”

Section: Notch and Mdscmentioning

confidence: 99%

Notch Signaling in Myeloid Cells as a Regulator of Tumor Immune Responses

Hossain

Majumder²,

Uçar

et al. 2018

Front. Immunol.

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Cancer immunotherapy, which stimulates or augments host immune responses to treat malignancies, is the latest development in the rapidly advancing field of cancer immunology. The basic principles of immunotherapies are either to enhance the functions of specific components of the immune system or to neutralize immune-suppressive signals produced by cancer cells or tumor microenvironment cells. When successful, these approaches translate into long-term survival for patients. However, durable responses are only seen in a subset of patients and so far, only in some cancer types. As for other cancer treatments, resistance to immunotherapy can also develop. Numerous research groups are trying to understand why immunotherapy is effective in some patients but not others and to develop strategies to enhance the effectiveness of immunotherapy. The Notch signaling pathway is involved in many aspects of tumor biology, from angiogenesis to cancer stem cell maintenance to tumor immunity. The role of Notch in the development and modulation of the immune response is complex, involving an intricate crosstalk between antigen-presenting cells, T-cell subpopulations, cancer cells, and other components of the tumor microenvironment. Elegant studies have shown that Notch is a central mediator of tumor-induced T-cell anergy and that activation of Notch1 in CD8 T-cells enhances cancer immunotherapy. Tumor-infiltrating myeloid cells, including myeloid-derived suppressor cells, altered dendritic cells, and tumor-associated macrophages along with regulatory T cells, are major obstacles to the development of successful cancer immunotherapies. In this article, we focus on the roles of Notch signaling in modulating tumor-infiltrating myeloid cells and discuss implications for therapeutic strategies that modulate Notch signaling to enhance cancer immunotherapy.

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Anti-Jagged Immunotherapy Inhibits MDSCs and Overcomes Tumor-Induced Tolerance

Cited by 68 publications

References 49 publications

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

Notch and NF-κB: Coach and Players of Regulatory T-Cell Response in Cancer

Identification of DeleteriousNOTCHMutation as Novel Predictor to Efficacious Immunotherapy in NSCLC

Notch Signaling in Myeloid Cells as a Regulator of Tumor Immune Responses

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