Converting Cold to Hot Tumor Microenvironment in Prostate Cancer by Targeting Chromatin Effector

项目摘要/摘要 转移性前列腺癌(PCA)仍然是无法治愈和致命的。使用免疫检查点进行免疫治疗 阻断(ICB)抗体使癌症治疗发生了革命性的变化，但先进的PCa对ICB治疗是困难的。主成分分析 有有限的效应细胞毒性T淋巴细胞(CTL)的渗透，这可能是ICB耐药的原因之一。 然而，对前列腺癌冷微环境的形成机制却知之甚少。最近，我们 发现1q21.3扩增子中的染色质效应因子PYGO2是前列腺癌(Lu)的致癌和转移驱动因素 等人，2018)。PYGO2与组蛋白H3结合，组蛋白H3尾部赖氨酸4(H3K4me)甲基化，调节转录。我们的 初步结果表明，PYGO2是一种控制免疫抑制和CTL的新兴信号中枢 Wnt/β-连环蛋白非依赖性的渗透，但前列腺癌中PYGO_2功能的确切机制 免疫逃避尚不清楚。此外，靶向PYGO2的选择性抑制剂对PCa进展的影响 对免疫治疗的反应也是未知的。因此，有很大的需要解开该功能， PYGO2的作用机制和靶向策略，以加强对PCa的免疫治疗。 我们的中心假设是PYGO2是一种主要的癌细胞-内在机制，它塑造了 PYGO2可显著增强PCa和ICB治疗中的免疫抑制微环境 使用新型小分子抑制剂的抑制作用。我们建议实现三个具体目标：(目标1)阐明 靶向和整合PYGO2在PCa免疫抑制中的表观遗传学机制 不带偏见的方法。(目的2)确定协同抗肿瘤作用对前列腺癌进展和转移的影响 采用PYGO2消融联合ICB治疗。目的3.鉴定具有抗PYGO2活性的小分子抑制剂 肿瘤活性作为单剂或联合免疫治疗。 项目完成后，我们希望阐明新的分子和细胞机制。 PYGO2在PCa肿瘤微环境免疫逃逸中的作用 联合靶向PYGO2和免疫检查点通路作为一种有效的新策略的临床前证据 联合免疫疗法，并确定使用时具有强大抗肿瘤活性的选择性PYGO2抑制剂 作为单一药物或与免疫疗法联合使用。我们的结果将促进对基因如何 癌细胞的变化(即PYGO2扩增)可以塑造寒冷的肿瘤微环境。给定 在许多癌症类型中，PYGO2的异常上调，我们的研究与大量癌症相关 病人。从长远来看，我们设想通过开发将我们的发现转化为床边工作 而PYGO2抑制剂(S)的临床试验可能会加速联合应用的治疗 表观遗传调控和免疫疗法对前列腺癌等癌症的根治治疗。

PROJECT SUMMARY/ABSTRACT Metastatic prostate cancer (PCa) remains incurable and lethal. Immunotherapy using immune checkpoint blockade (ICB) antibodies revolutionized cancer treatment, yet advanced PCa is refractory to ICB therapy. PCa has limited infiltration of effector cytotoxic T lymphocytes (CTLs), which may contribute to ICB resistance. However, the mechanism shaping the cold microenvironment of PCa is poorly understood. Recently, we identified chromatin effector PYGO2 in the 1q21.3 amplicon as an oncogenic and metastatic driver for PCa (Lu et al, 2018). PYGO2 binds to histone H3 tail methylated at lysine 4 (H3K4me) and modulates transcription. Our preliminary results suggest that PYGO2 is an emerging signaling hub to control immunosuppression and CTL infiltration in a Wnt/β-catenin-independent manner, yet the precise mechanism for PYGO2 function in PCa immune evasion is unclear. Moreover, the effect of targeting PYGO2 with selective inhibitors on PCa progression and response to immunotherapy is unknown. Therefore, there is a significant need to unravel the function, mechanism and targeting strategy of PYGO2 in order to enhance immunotherapy of PCa. Our central hypothesis is that PYGO2 is a major cancer cell-intrinsic mechanism to shape the immunosuppressive microenvironment in PCa, and ICB therapy can be significantly enhanced by PYGO2 inhibition using novel small molecule inhibitors. We propose to accomplish three Specific Aims: (Aim 1) Elucidate the epigenetic mechanism of PYGO2 function in the immunosuppression of PCa by integrating targeted and unbiased approaches. (Aim 2) Determine the synergistic anti-tumor effect on PCa progression and metastasis by combining PYGO2 ablation and ICB therapy. (Aim 3) Identify small molecule inhibitors of PYGO2 with anti- tumor activity as single agent and in combination with immunotherapy. Upon completion of the project, we expect to illuminate novel molecular and cellular mechanisms underlying the role of PYGO2 in immune evasion of the PCa tumor microenvironment, establish the key preclinical evidence on co-targeting PYGO2 and immune checkpoint pathways as a new strategy of effective combination immunotherapy, and identify selective PYGO2 inhibitors with potent anti-tumor activity when used as single agent or in combination with immunotherapy. Our results will advance understanding of how genetic changes in cancer cells (i.e. PYGO2 amplification) can shape the cold tumor microenvironment. Given the aberrant upregulation of PYGO2 in many cancer types, our studies are relevant to a large population of cancer patients. In the long term, we envision that the bench-to-bedside translation of our findings through development and clinical testing of the PYGO2 inhibitor(s) may accelerate the therapeutic application of the combined epigenetic modulation and immunotherapy to the curative treatment of PCa and other cancers.