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.

项目总结/摘要 治疗失败仍然是侵袭性三阴性乳腺癌患者的首要临床挑战 癌症（TNBC）。调节TNBC转移和复发的两个重要因素是： 癌细胞的状态，和（ii）抗肿瘤免疫的功能，这两者都受到 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）在调节癌细胞分化和免疫系统功能方面是相互对立的 在TNBC。TGFβ及其受体在侵袭性、治疗抗性癌症中经常上调，例如 TNBC。从机制上讲，我们发现TGFβ效应子SMAD 3与STAT 3协同作用，而STAT 3是TGF β的重要效应子。 IL-6家族的细胞因子，以诱导干细胞样/间充质重编程，这增强了TNBC侵袭性， 肿瘤引发能力和治疗抗性。同时，TGFβ强烈抑制IFNβ 生产由于IFNβ促进较低侵袭性的癌细胞状态并激活抗肿瘤免疫， TGFβ介导的对IFNβ及其下游效应物STAT 1和STAT 2的抑制是一种重要的免疫抑制剂。 导致TNBC进展和免疫系统受损。重要的是，IFNβ信号的恢复 导致TGFβ介导的干细胞样/间充质程序逆转，并重新参与抗肿瘤免疫。 我们假设肿瘤细胞和免疫细胞中TGFβ和IFNβ细胞因子活性的相对量 决定了TNBC的侵略性，并最终决定了患者的结局。我们研究的目的是确定 TGFβ和IFNβ在调节干细胞样/间充质细胞中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有很强的联系，项目1将评估 通过一种新的苏氨酸磷酸化调节STAT 2，并与项目3，这将检查如何TGFβ 与另一种促肿瘤细胞因子IL-17协同作用，以放大抑制IFNβ产生的关键信号。 在我们的计划中提出的统一研究将（i）确定共同的分子机制，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 旨在改变TME中IFNβ和TGFβ/IL-17信号传导的平衡。通过改变这种平衡，我们 建议诱导癌细胞分化，增强抗肿瘤免疫力，增加敏感性 难以治疗的癌症转移到化疗和免疫疗法。