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: 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
• 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

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.

项目概要/摘要 对于侵袭性三阴性乳腺癌患者来说，治疗失败仍然是一个首要的临床挑战 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）抗肿瘤免疫力，两者都受到以下因素的高度影响： 我们发现 TME 细胞因子转化生长因子 β (TGFβ) 和 干扰素 β (IFNβ) 在调节癌细胞分化和免疫系统功能方面相互对抗 在 TNBC 中，TGFβ 及其受体在侵袭性、难治性癌症中经常上调，例如 从机制上讲，我们发现 TGFβ 效应子 SMAD3 与 STAT3 合作，STAT3 是 TNBC 的重要效应子。 IL-6 细胞因子家族，诱导干样/间质重编程，从而增强 TNBC 侵袭性， 同时，TGFβ 强烈抑制 IFNβ。 由于 IFNβ 可以促进癌细胞处于侵袭性较低的状态并激活抗肿瘤免疫，因此 TGFβ 介导的 IFNβ 及其下游效应子 STAT1 和 STAT2 的抑制是重要的 导致 TNBC 进展和免疫系统损伤的重要因素是 IFNβ 信号传导的恢复。 导致 TGFβ 介导的干细胞样/间充质程序逆转并重新启动抗肿瘤免疫。 我们研究了癌症和免疫细胞中 TGFβ 和 IFNβ 细胞因子活性的相对量 决定 TNBC 的侵袭性并最终决定患者的结果。我们研究的目的是定义 TNBC 的侵袭性。 TGFβ和IFNβ相互拮抗调节干细胞/间质细胞的分子机制 我们的项目与项目 1 有着密切的联系，项目 1 将评估 通过新型苏氨酸磷酸化调节 STAT2，项目 3 将研究 TGFβ 如何调节 与另一种促肿瘤细胞因子 IL-17 协同作用，放大对于抑制 IFNβ 产生至关重要的信号。 我们的计划中提出的统一研究将（i）确定促进 对化疗和免疫疗法产生耐药性，以及 (ii) 评估新的治疗组合 通过改变这种平衡，我们的目标是改变 TME 中 IFNβ 和 TGFβ/IL-17 信号传导的平衡。 提出诱导癌细胞分化，增强抗肿瘤免疫力，增加敏感性 难以治疗的癌症需要化疗和免疫治疗。