Targeting the cGAS/STING Pathway to Overcome Resistance to Immune Checkpoint Inhibitors in PTEN-deficient Prostate Cancer

靶向 cGAS/STING 通路克服 PTEN 缺陷前列腺癌对免疫检查点抑制剂的耐药性

• 批准号: 10504904
• 负责人: Akash Patnaik
• 金额: $ 53.47万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10504904
• 关键词: Agonist; Antibodies; Antitumor Response; Bypass; Cancer Patient; Cells; Clinical; Clinical Research; Clinical Trials; Combined Modality Therapy; Cyclic GMP; DNA; DNA Damage; DNA Double Strand Break; Data; Disease; Foundations; Gene Activation; Generations; Genetically Engineered Mouse; Goals; Immune; Immune checkpoint inhibitor; Immunotherapeutic agent; Infiltration; Knock-out; Macrophage Activation; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Modeling; Mus; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Natural Immunity; Nature; Nivolumab; PARP inhibition; PTEN gene; Pathway interactions; Patients; Pre-Clinical Model; Prognosis; Prostate; Repression; Research Personnel; Resistance; Sampling; Signal Transduction; Stimulator of Interferon Genes; Surface; Testing; Therapeutic; Tumor-associated macrophages; Tumor-infiltrating immune cells; Variant; anti-cancer; base; cancer cell; castration resistant prostate cancer; combinatorial; extracellular vesicles; loss of function; macrophage; mouse model; multiple omics; neoplastic cell; pre-clinical; preclinical study; prevent; programmed cell death protein 1; prostate cancer model; refractory cancer; replication stress; resistance mechanism; response; scavenger receptor; subcutaneous; therapy outcome; tumor; tumor microenvironment; vesicular release

PROJECT SUMMARY/ABSTRACT: Immune checkpoint inhibitors (ICI) are active in only 10-25% of metastatic, castrate-resistant prostate cancer (mCRPC) patients. Co-clinical immune profiling studies of the tumor microenvironment (TME) in mCRPC patients and murine PC models demonstrated sparse immune infiltrates, with predominance of immunosuppressive myeloid cells, particularly tumor-associated macrophages (TAM). PTEN loss-of-function (LOF) occurs in multiple cancers, and specifically in 50-75% of mCRPC. It is associated with poor prognosis, therapeutic outcomes and de novo/acquired resistance to ICI in preclinical and clinical studies in multiple tumor types. In addition to the predominance of TAM within the sparse immune infiltrate in PC, we observed a 2-fold increase of myeloid derived suppressor cells within the PTEN LOF TME, relative to isogenic PTEN-proficient counterparts. These data reinforced our project goal of elucidating mechanisms underlying altered cancer/myeloid cell cross-talk in PTEN LOF mCRPC, that are likely similar across PTEN-deleted malignancies and contribute to ICI resistance. We have demonstrated that cyclic GMP-AMP Synthase (c-GAS)/Stimulator of INterferon Genes (STING) pathway, typically activated in response to cytosolic DNA double strand breaks (DSB), is frequently silenced in cancer cells, and cGAS/STING activation within myeloid compartment of the TME is critical for generating a robust immune infiltrate. However, generation of DNA DSB is insufficient to enhance T cell infiltration, which is consistent with lack of response to PARP inhibition (PARPi) plus ICI observed in our murine models and clinical studies. Probing more deeply into this disconnect, we found that failed STING pathway activation within TAM was responsible for this resistance. Furthermore, PI3K activity was preventing STING pathway activation in TAM, and PI3K inhibition (PI3Ki) plus DNA damage with PARPi led to ICI responsiveness in PTEN-proficient, but not in isogenic PTEN-knockout PC, suggesting that additional immunosuppressive mechanisms are driven by PTEN LOF. The central hypothesis of this proposal is that PTEN LOF PC are de novo resistant to DNA DSB sensing c-GAS/STING pathway activation, which can be overcome by direct STING agonist-based combinations, leading to ICI sensitization. To test this hypothesis, we propose the following specific aims. First, we will dissect the TME in a completed investigator-initiated clinical trial of PARPi/ICI in mCRPC patients, to determine whether the immune inhibitory mechanisms identified in preclinical models are relevant to patients. Second, we will elucidate the cancer cell extrinsic mechanism(s) by which PTEN-deficient PC are de novo resistant to DNA-sensing STING pathway activation. Third, we will interrogate the anti-cancer mechanism and therapeutic potential of direct STING agonist/PI3Ki combination therapy in sensitizing PTEN-knockout murine CRPC to ICI. Collectively, these “co-clinical” studies will provide the mechanistic foundation for the next wave of immunotherapeutic strategies to eradicate PTEN LOF mCRPC.

项目摘要/摘要： 免疫检查点抑制剂 (ICI) 仅对 10-25% 的转移性去势抵抗性前列腺有活性 mCRPC 患者肿瘤微环境 (TME) 的临床联合免疫分析研究。 患者和小鼠 PC 模型表现出稀疏的免疫浸润，主要是 免疫抑制性骨髓细胞，特别是肿瘤相关巨噬细胞 (TAM) 功能丧失。 (LOF) 发生在多种癌症中，特别是 50-75% 的 mCRPC 中，它与不良预后相关。 多种肿瘤的临床前和临床研究中的治疗结果和对 ICI 的从头/获得性耐药 除了 TAM 在 PC 中稀疏的免疫浸润中占主导地位之外，我们还观察到 2 倍。 相对于等基因 PTEN 熟练者，PTEN LOF TME 中骨髓源性抑制细胞的增加 这些数据强化了我们阐明潜在机制的项目目标 PTEN LOF mCRPC 中的癌症/骨髓细胞串扰，在 PTEN 缺失的恶性肿瘤中可能相似 并有助于 ICI 抵抗。 我们已经证明环 GMP-AMP 合酶 (c-GAS)/干扰素基因刺激剂 (STING) 该途径通常响应胞质 DNA 双链断裂 (DSB) 而被激活，但在 癌细胞，TME 髓样区室内的 cGAS/STING 激活对于产生 然而，DNA DSB 的产生不足以增强 T 细胞浸润。 与我们在小鼠模型和临床中观察到的对 PARP 抑制 (PARPi) 加上 ICI 缺乏反应的情况一致 通过更深入地研究这种脱节，我们发现 TAM 内的 STING 通路激活失败。 此外，PI3K 活性阻止了 TAM 中 STING 通路的激活， PI3K 抑制 (PI3Ki) 加上 PARPi 的 DNA 损伤导致 PTEN 熟练的 ICI 反应，但没有 在同基因 PTEN 敲除 PC 中，表明 PTEN 驱动其他免疫抑制机制 LOF 该提案的中心假设是 PTEN LOF PC 对 DNA DSB 传感具有从头抵抗性。 c-GAS/STING 通路激活，可以通过直接基于 STING 激动剂的组合来克服，导致 为了检验这一假设，我们提出以下具体目标：首先，我们将剖析 TME。 在一项由研究者发起的针对 mCRPC 患者的已完成的 PARPi/ICI 临床试验中，以确定是否 其次，我们将阐明临床前模型中确定的免疫抑制机制与患者相关。 PTEN 缺陷型 PC 对 DNA 感应 STING 产生从头抵抗的癌细胞外在机制 第三，我们将探讨直接疗法的抗癌机制和治疗潜力。 STING 激动剂/PI3Ki 联合疗法使 PTEN 敲除小鼠 CRPC 对 ICI 敏感。 “联合临床”研究将为下一波免疫治疗策略提供机制基础 根除 PTEN LOF mCRPC。