Targeting UHRF1 in combinational immunotherapy

免疫检查点阻断疗法在治疗黑色素瘤方面取得了前所未有的成功 和肺癌。然而，令人兴奋的是，即使联合抑制PD-1和CTLA4，也只有一种 部分癌症患者被观察到有客观反应，其中更少的人 达到长期缓解期。因此，当务之急是确定确定 检查点靶向的有效性，并开发新的治疗策略，与当前的 治疗。虽然检查站封锁抵抗的机制还没有得到准确的确定 通过任何新的生物标志物的变化，人们达成了一种共识，即更有利的反应是 观察T细胞发炎的“热”瘤患者。在分子水平上，发炎的肿瘤 微环境的特征是T细胞和NK细胞的激活，它们是细胞溶解功能的效应分子， T和NK细胞募集的趋化因子、I型干扰素(干扰素-I)和干扰素反应基因。这个 干扰素-I的抗病毒作用是在几十年前发现的，而其抗肿瘤机制是最近才发现的。 已澄清。新兴的科学前提支持这样一种假设，即存在一种看似合理的战略来 改善肿瘤的免疫“准备”，克服肿瘤对检查点封锁的抵抗力 通过提高瘤内干扰素-I水平进行治疗。在这方面，我们的初步结果表明， 抑制一种表观遗传修饰物泛素样PHD和环指结构域1的表达 (Uhrf1)，在肺癌细胞中极大地触发干扰素-I反应，并最终进入肿瘤内T细胞 积累。令人惊讶的是，uhrf1缺陷的肿瘤细胞也对干扰素诱导的PD-L1产生了抵抗力。 表面表达。此外，uhrf1的基因缺失会损害血管内皮细胞的增殖和功能。 调节性T细胞(ITregs)，肿瘤中的一种间质细胞群，它执行 免疫抑制功能。综上所述，我们假设以uhrf1为目标表示 逆转肿瘤微环境中免疫抑制的综合策略。在这项研究中，我们 我将通过三个具体目标来检验这一假设。目标1将确定分子机制，通过它 肿瘤uhrf1重塑肿瘤微环境。目标2将决定通过什么机制 Uhrf1调节T细胞活化。目标3将确定一种治疗策略的临床前疗效 联合抑制uhrf1和PD-1或CTLA-4对肺癌的抑制作用。因为一个小分子 已开发出uhrf1抑制剂样机，该项目的成功将建立一种新的和 为肿瘤微环境再规划的可行目标，并为结合奠定科学基础 针对肺癌的检查站封锁治疗。

Immune checkpoint blockade therapy has delivered unprecedented success in the treatment of melanoma and lung cancer. However, as exciting as this is, even with combined inhibition of PD-1 and CTLA4, only a portion of cancer patients were observed with objective responses and an even smaller percentage of them reached long term remission. Therefore, it is imperative to identify specific mechanisms that determine the efficacy of checkpoint targeting, and to develop novel therapeutic strategies synergizing with current treatments. Although the mechanism of checkpoint blockade resistance has not been precisely determined by changes in any novel biomarkers, a consensus has been reached that more favorable responses are observed in patients with T cell-inflamed ”hot” tumors. At the molecular level, the inflamed tumor microenvironment is characterized by activation of T and NK cells, effector molecules for cytolytic functions, chemokines for T and NK cell recruitment, type I interferons (IFN-I), and interferon-responsive genes. The anti-virus role of IFN-I was discovered decades ago, whereas its anti-tumor mechanism was more recently elucidated. The emerging scientific premise supports the hypothesis that there exists a plausible strategy to improve the immune “readiness” of a tumor, and to overcome tumor resistance to checkpoint blockade therapy by elevating the level of intratumoral IFN-I. In this regard, our preliminary results show that inhibiting the expression of one epigenetic modifier, ubiquitin like with PHD and ring finger domains 1 (UHRF1), in lung cancer cells dramatically triggers IFN-I responses and ultimately intratumoral T cell accumulation. Surprisingly, UHRF1 deficient tumor cells also become resistant to IFN-I-induced PD-L1 surface expression. Furthermore, genetic deletion of UHRF1 impairs the proliferation and function of regulatory T cells (iTregs), a stromal cell population in the tumor mass that carries out an immunosuppressive function. Taken together, we hypothesize that targeting UHRF1 represents a comprehensive strategy to reverse immunosuppression in the tumor microenvironment. In this study, we will test this hypothesis by three specific aims. Aim 1 will determine molecular mechanisms through which tumoral UHRF1 remodels the tumor microenvironment. Aim 2 will determine the mechanism by which UHRF1 regulates T cell activation. Aim 3 will determine the pre-clinical efficacy of a therapeutic strategy combining UHRF1 suppression and PD-1 or CTLA-4 blockade against lung cancer. Since a small molecule UHRF1 inhibitor prototype has been developed, the success of this project will establish a novel and feasible target for tumor microenvironmental reprogramming, and lay a scientific foundation for combination therapy with checkpoint blockade against lung cancer.