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

项目摘要/摘要 治疗失败仍然是侵袭性三阴乳房患者面临的首要临床挑战 癌症(TNBC)。调节TNBC转移和复发的两个重要因素是：(I)分化程度 癌细胞的状态，以及(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(β)和 干扰素β对肿瘤细胞分化和免疫系统功能的调节作用相互对立 在TNBC。转化生长因子β及其受体经常在侵袭性的、耐药的癌症中上调，如 TNBC。在机制上，我们发现转化生长因子β效应器Smad3与STAT3协同作用，STAT3是Smad3的重要效应器。 IL-6家族的细胞因子，诱导干样/间充质重编程，从而增强TNBC的侵袭性， 肿瘤启动能力和治疗抵抗力。同时，转化生长因子β对干扰素β有强烈的抑制作用 制作。由于干扰素β促进较不具侵袭性的癌细胞状态并激活抗肿瘤免疫，因此 转化生长因子β介导的干扰素β及其下游效应分子STAT1和STAT2的抑制是一个重要的 导致TNBC进展和免疫系统损害的因素。重要的是，干扰素β信号的恢复 结果逆转转化生长因子β介导的干细胞/间充质细胞程序，并重新启动抗肿瘤免疫。 我们推测肿瘤细胞和免疫细胞中转化生长因子β和干扰素β细胞因子活性的相对量 决定TNBC的进攻性，并最终决定患者的预后。我们研究的目的是定义 转化生长因子β和干扰素β相互拮抗调节干细胞/间充质的分子机制 重新编程和抗肿瘤免疫。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STAT2，以及研究转化生长因子β如何 与另一种促肿瘤细胞因子IL-17协同作用，放大抑制干扰素β产生的关键信号。 我们计划中提出的统一研究将：(I)确定共同的分子机制，促进 化疗和免疫治疗的抗药性的发展和(Ii)评估新的治疗组合 目的：改变TME中干扰素β和转化生长因子β/IL-17信号的平衡。通过改变这种平衡，我们 建议通过诱导癌细胞分化和增强抗肿瘤免疫来提高敏感性 从难以治疗的癌症到化疗和免疫治疗。

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.