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

• 批准号: 10704231
• 负责人: MARK W. JACKSON
• 金额: $ 39.32万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 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/10704231
• 关键词: Adjuvant Chemotherapy; Animal Model; Binding; Binding Sites; Breast Cancer Model; Breast cancer metastasis; Cells; Chromatin; Clinical; Combined Modality Therapy; Dissection; Epithelium; Equilibrium; Family; Gene Expression; Genes; Genetic Transcription; Goals; IL17 gene; Immune; Immune checkpoint inhibitor; Immune system; Immunosuppression; Immunotherapy; Impairment; Interferon Activation; Interferon-beta; Interferons; Interleukin-6; MADH3 gene; Malignant Neoplasms; Mediating; Mesenchymal; Messenger RNA; Molecular; Neoadjuvant Therapy; Patient-Focused Outcomes; Patients; Phosphorylation; Production; RNA Binding; Recurrence; Recurrent Malignant Neoplasm; Regulation; Repression; Resistance development; STAT1 gene; STAT2 gene; STAT3 gene; Signal Transduction; Specimen; Standardization; Sting Injury; Stromal Cells; TGFB1 gene; Testing; Threonine; Time; Transforming Growth Factor beta; Translations; Treatment Failure; Tumor Immunity; Viral; aggressive breast cancer; 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; synergism; therapy resistant; triple-negative invasive breast carcinoma; tumor; tumor initiation; tumor microenvironment

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.

项目摘要/摘要 治疗失败仍然是侵略性三重负乳房患者的总体临床挑战 癌症（TNBC）。调节TNBC转移和复发的两个重要因素是：（i）分化 癌细胞的状态，以及（ii）抗肿瘤免疫学的功能，两者都受到高度影响 肿瘤微环境（TME）。我们发现TME细胞因子转化生长因子β（TGFβ）和 干扰素β（IFNβ）在控制癌细胞分化和免疫系统功能方面相互反对 在TNBC中。 TGFβ及其受体经常在侵略性，耐药的癌症中进行更新，例如 TNBC。从机械上讲，我们发现TGFβ效应子SMAD3与STAT3合作，STAT3是一个重要的效应子 IL-6细胞因子家族，诱导茎状/间充质重编程，从而增强TNBC的侵入性， 肿瘤发射能力和治疗性抗性。同时，TGFβ强烈抑制IFNβ 生产。由于IFNβ促进了侵袭性较低的癌细胞态并激活抗肿瘤免疫力，因此 TGFβ介导的IFNβ及其下游效应STAT1和STAT2的抑制是重要的 TNBC进展和免疫系统损害的贡献者。重要的是，IFNβ信号的恢复 导致TGFβ介导的茎状/间充质程序的逆转并重新引入抗肿瘤免疫学。 我们假设癌症和免疫细胞中TGFβ和IFNβ细胞因子活性的相对量 决定TNBC的侵略性，最终决定患者的结果。我们研究的目的是定义 TGFβ和IFNβ在控制茎样/间充质方面相互拮抗的分子机制 重编程和抗肿瘤免疫。我们的项目与项目1有密切的联系，该项目将评估 通过新型苏氨酸磷酸化对STAT2进行调节，并通过项目3来研究TGFβ如何 与另一种促肿瘤细胞因子IL-17协同作用，以扩大表达IFNβ产生至关重要的信号。 我们计划中提出的统一研究将（i）确定促进促进的共同分子机制 对化学和免疫治疗以及（ii）评估新型热组合的抗性发展 旨在转移TME中IFNβ和TGFβ/IL-17信号的等效。通过改变这种平衡，我们 提出诱导癌细胞分化并增强抗肿瘤免疫以提高灵敏度的建议 难以治疗的癌症进行化学和免疫治疗。