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Shifting the balance between IFN-I and TGF-beta to improve cancer therapy

改变 IFN-I 和 TGF-β 之间的平衡以改善癌症治疗

基本信息

批准号：
10493939
负责人：
MARK W. JACKSON
金额：
$ 40.09万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-13 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10493939
关键词：
Animal Model Binding Binding Sites Breast Cancer Model Breast cancer metastasis Cells Chromatin Clinical Complement Factor B Dissection Epithelial Equilibrium Family Gene Expression Genes Genetic Transcription Goals Immune Immune checkpoint inhibitor Immune system Immuno-Chemotherapy Immunosuppression Immunotherapy Impairment Interferon Suppression Interferon-beta Interferons Interleukin-17 Interleukin-6 MADH3 gene Malignant Neoplasms Mediating Mesenchymal Messenger RNA Molecular Neoadjuvant Therapy Patient-Focused Outcomes Patients Phosphorylation Production RNA Binding Recurrence Regulation Repression Resistance development STAT1 gene STAT2 gene STAT3 gene Signal Transduction Specimen Standardization Stromal Cells Testing Threonine Time Transforming Growth Factor beta Transforming Growth Factors Translations Treatment Failure Tumor Immunity Viral aggressive therapy autocrine breast cancer progression cancer cell cancer cell differentiation cancer invasiveness cancer recurrence cancer therapy cell behavior chemotherapy cytokine epigenomics immune system function improved improved outcome in vivo mimicry novel novel therapeutic intervention novel therapeutics paracrine prevent programs receptor refractory cancer response restoration sensor standard of care stem therapy resistant triple-negative invasive breast carcinoma tumor tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Therapy failure remains an overarching clinical challenge for patients with aggressive Triple Negative Breast Cancer (TNBC). Two important factors that regulate TNBC metastasis and recurrence are: (i) the differentiation status of the cancer cells, and (ii) the functionality of anti-tumor immunity, both of which are highly influenced by the tumor microenvironment (TME). We find that the TME cytokines Transforming Growth Factor β (TGFβ) and Interferon β (IFNβ) oppose one another in regulating both cancer cell differentiation and immune system function in TNBC. TGFβ and its receptors are frequently upregulated in aggressive, therapy-resistant cancers, such as TNBC. Mechanistically, we find that TGFβ effector SMAD3 cooperates with STAT3, an important effector of the IL-6 family of cytokines, to induce stem-like/mesenchymal reprogramming, which enhances TNBC invasiveness, tumor-initiating capacity, and therapeutic resistance. At the same time, TGFβ strongly suppresses IFNβ production. Since IFNβ promotes a less aggressive cancer cell state and activates anti-tumor immunity, the TGFβ-mediated suppression of IFNβ and its downstream effectors, STAT1 and STAT2, is an important contributor to TNBC progression and immune system impairment. Importantly, restoration of IFNβ signaling results in the reversal of TGFβ-mediated stem-like/mesenchymal program and re-engages anti-tumor immunity. We hypothesize that the relative amounts of TGFβ and IFNβ cytokine activity in both cancer and immune cells dictate TNBC aggressiveness and ultimately, patient outcomes. The purpose of our study is to define the molecular mechanisms by which TGFβ and IFNβ antagonize one another in regulating stem-like/mesenchymal reprogramming and anti-tumor immunity. Our Project has strong connections with Project 1, which will assess the regulation of STAT2 by a novel threonine phosphorylation, and with Project 3 which will examine how TGFβ synergizes with another pro-tumor cytokine, IL-17, to amplify the signals critical for repressing IFNβ production. The unifying studies proposed in our Program will (i) identify common molecular mechanisms that promote the development of resistance to chemo- and immune-therapies and (ii) assess novel therapeutic combinations aimed at shifting the equilibrium of IFNβ and TGFβ/IL-17 signaling in the TME. By shifting this balance, we propose to induce the differentiation of cancer cells and enhance anti-tumor immunity to increase the sensitivity of hard-to-treat cancers to chemo- and immuno-therapy.

项目总结/文摘