Exploring novel therapeutic strategies for combinatory therapy to treat renal clear cell carcinomas

项目摘要-摘要 肾细胞癌(RCC)是男性(第6位)和女性(第8位)最常见的10种癌症之一。 全世界。大多数肾细胞癌是透明细胞癌(80%)，在许多方面代表了一种不典型的癌症类型 包括对多种化疗药物的内在耐药性，对抗新生血管生成的敏感性，以及敏感性 对免疫检查点抑制剂，但突变负担非常低。碾压混凝土的处理景观已被 在过去几年中变化很快，但完全响应率仍然很低，即使是最 更新了治疗方案。RCC的这些“非典型”特征促使我们表演了一首全面的单曲 人肾小管细胞癌和配对血液的细胞RNA测序。我们发现肿瘤诱导的树突状细胞高度 抑制效应T细胞，可能是免疫抑制性肿瘤的主要免疫细胞 微环境(TME)。这些TI-Treg具有典型的细胞衰老迹象，包括表达 P16、p21、bclxl、衰老相关分泌表型和β-半乳糖苷酶的激活 (β-Gal)。该小组最近报告了一流的bcl-xl降解物的开发，即蛋白质分解 靶向嵌合体(PROTAC，简称BCL-XL-Ps)。DT2216，一个领先的BCL-XL-P，目标是BCL-XL到 Von Hippel-Lindau(VHL)E3连接酶；PZ15227靶向BCL-XL到Cereblon(CRBN)E3连接酶 蛋白酶体的泛素化和随后的降解。我们发现这两种感光剂非常 在我们最近的出版物中，有效地消除了TI-Tregs并激活了抗肿瘤免疫。基于这些小说 发现，我们假设与衰老和癌症相关的细胞衰老-包括来自 免疫细胞--通过调节肿瘤免疫，在肾癌发病和肿瘤进展中起关键作用 微环境。了解这些基本问题对于合理设计治疗性药物具有重要意义。 向肾细胞癌的治疗方案仍然是一个迫切且未得到满足的临床需求。具体目标1是建立 细胞衰老--尤其是Treg衰老--与肾细胞癌之间的机制联系 注重对肿瘤免疫微环境的调节。目的2是确定该药的治疗效果 肾细胞癌中TI-Tregs的溶细胞耗竭和常用治疗方法。该团队在临床肾癌方面拥有专业知识， 细胞衰老，特别是衰老药物的开发和衰老示踪，癌症模型和 癌症免疫学。我们将确定肿瘤浸润性树突状细胞在肿瘤内免疫调节中的作用 微环境和确定靶向衰老树突状细胞在肾细胞癌治疗中的疗效 使用抗新生血管药物或免疫检查点抑制剂。

Project Summary-Abstract Renal cell carcinomas (RCC) are among the 10 most common cancer types in man (6th) and woman (8th) worldwide. Most RCC are clear cell carcinomas (>80%) that represent an atypical cancer type in many ways including the intrinsic resistance to many chemotherapeutics, sensitivity to anti-neoangiogenesis, and sensitivity to immune checkpoint inhibitors but with very low mutational burden. The treatment landscape of RCC has been changing rapidly in the last couple of years but still with very low complete response rate even with the most updated treatment regimens. Those “atypical” features of RCC prompted us to perform a comprehensive single cell RNA sequencing for human ccRCCs and paired bloods. We found that tumor induced Tregs are highly suppressive to effector T cells and could be the major immune cells conferring the immune suppressive tumor microenvironment (TME). These TI-Tregs have the typical signs of cellular senescence, including the expression of p16, p21, BCL-XL, senescence-associated secretory phenotype (SASP), and the activation of β-galactosidase (β-Gal). The group recently reported the development of the first-in-class BCL-XL degraders, i.e. the Proteolysis Targeting Chimeras (PROTACs, referred to as BCL-XL-Ps). DT2216, a lead BCL-XL-P, targets BCL-XL to the von Hippel-Lindau (VHL) E3 ligase; and PZ15227 targets BCL-XL to the cereblon (CRBN) E3 ligase for ubiquitination and subsequent degradation by the proteasome. We have found these two senolytics are very effective in eliminating TI-Tregs and activate anti-tumor immunity in our recent publication. Based on these novel findings, we hypothesize that aging- and cancer-associated cellular senescence – including senescence from immune cells – is critical in RCC pathogenesis and cancer progression via modulating the tumor immune microenvironment. Understanding these fundamental questions is important for rational design of therapeutic regimens towards to RCC that remains an urgent and unmet clinical need. Specific Aim 1 is to establish the mechanistic connection between cellular senescence – in particular Treg senescence – and RCC with special focus on the modulation of tumor immune microenvironment. Aim 2 is to determine the therapeutic efficacy of senolytic depletion of TI-Tregs and common therapeutics in RCC. The team has expertise in clinical renal cancer, cellular senescence, in particular the senolytic drug development and senescence tracing, cancer models and cancer immunology. We will establish the role of tumor infiltrating Tregs in immune modulation within the tumor microenvironment and determine the efficacy of targeting senescent Tregs in RCC cancer therapy, by combining with anti-neoangiogenesis drugs or immune checkpoint inhibitors.