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

项目概要/摘要 转移性前列腺癌（PCa）仍然是不可治愈和致命的。使用免疫检查点的免疫疗法 阻断（ICB）抗体彻底改变了癌症治疗，但晚期PCa对ICB疗法是难治的。PCA 具有有限的效应细胞毒性T淋巴细胞（CTL）浸润，这可能有助于ICB抗性。 然而，形成PCa冷微环境的机制知之甚少。最近我们 在1q21.3扩增子中鉴定了染色质效应PYGO 2作为PCa的致癌和转移驱动因子（Lu 等人，2018）。PYGO 2与组蛋白H3尾部赖氨酸4甲基化（H3 K4 me）结合并调节转录。我们 初步结果表明PYGO 2是一个新兴的信号中枢，控制免疫抑制和CTL PCa中PYGO 2以Wnt/β-catenin非依赖性方式浸润，但PCa中PYGO 2功能的确切机制 免疫逃避尚不清楚。此外，用选择性抑制剂靶向PYGO 2对PCa进展的影响 对免疫疗法的反应尚不清楚。因此，非常需要解开该功能， PYGO 2的作用机制和靶向策略，以增强PCa的免疫治疗。 我们的中心假设是PYGO 2是一种主要的癌细胞内在机制， PYGO 2可显著增强PCa中的免疫抑制微环境和ICB治疗 使用新型小分子抑制剂进行抑制。我们建议实现三个具体目标：（目标1）阐明 PYGO 2在PCa免疫抑制中的表观遗传学机制是通过整合靶向和 无偏见的方法。(Aim 2）确定对PCa进展和转移的协同抗肿瘤作用 PYGO 2消融和ICB治疗相结合。(Aim 3）鉴定PYGO 2的小分子抑制剂， 单独使用以及与免疫疗法联合使用的肿瘤活性。 在项目完成后，我们希望阐明新的分子和细胞机制 PYGO 2在PCa肿瘤微环境的免疫逃避中的作用， 共同靶向PYGO 2和免疫检查点通路作为有效治疗的新策略的临床前证据 联合免疫疗法，并鉴定在使用时具有强效抗肿瘤活性的选择性PYGO 2抑制剂 作为单一药剂或与免疫疗法组合。我们的研究结果将进一步了解遗传 癌细胞的变化（即PYGO 2扩增）可以塑造冷肿瘤微环境。鉴于 PYGO 2在许多癌症类型中的异常上调，我们的研究与大量癌症相关。 患者从长远来看，我们设想，通过发展， 并且PYGO 2抑制剂的临床试验可加速组合药物的治疗应用。 表观遗传调节和免疫疗法用于PCa和其他癌症的治愈性治疗。

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.