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）仅在10-25％的转移性，耐Castrate的前列腺中活跃 癌症（MCRPC）患者。 MCRPC中肿瘤微环境（TME）的共同链接免疫分析研究 患者和鼠PC模型表现出稀疏的免疫浸润，占主导地位 免疫抑制髓样细胞，尤其是肿瘤相关的巨噬细胞（TAM）。 PTEN功能丧失 （LOF）发生在多种癌症中，特别是在MCRPC的50-75％中发生。它与预后不良有关 在多个肿瘤的临床前和临床研究中，治疗结果和从头/获得的ICI抗性 类型。除了在PC中稀疏免疫浸润内TAM的占主导地位外，我们观察到了2倍 相对于等源性PTEN生产能力，在PTEN LOF TME内增加髓样衍生的抑制细胞 同行。这些数据加强了我们阐明改变基础机制的项目目标 PTEN LOF MCRPC中的癌症/髓样细胞串扰，它们在PTEN删除的malignancys中可能相似 并有助于ICI抗性。 我们已经证明了干扰素基因（sting）的环状GMP-AMP合酶（C-GAS）/刺激剂 通常是针对胞质DNA双链断裂（DSB）激活的途径，经常在 癌细胞，TME髓样区内的CGA/刺激激活对于产生A至关重要 强大的免疫浸润。但是，DNA DSB的产生不足以增强T细胞浸润，这是 与缺乏对PARP抑制的反应（PARPI）以及在我们的鼠模型和临床中观察到的ICI一致 研究。在此断开连接中更深入地探索，我们发现TAM内的刺激途径失败 负责这种抵抗。此外，PI3K活性阻止了TAM的刺激途径激活 和PI3K抑制（PI3KI）加上PARPI的DNA损伤导致PTEN响应能力，但没有 在等源性PTEN-KNOCKOUT PC中，这表明其他免疫抑制机制是由PTEN驱动的 洛夫。该提议的中心假设是PTEN LOF PC对DNA DSB传感器具有抗性 C-GAS/STING途径激活，可以通过直接刺激激动剂组合来克服，并领导 进行ICI传感器。为了检验这一假设，我们提出了以下特定目标。首先，我们将剖析TME 在一项完整的研究人员在MCRPC患者中对PARPI/ICI的临床试验中，以确定是否是否 临床前模型中鉴定出的免疫抑制机制与患者有关。其次，我们将阐明 缺乏PTEN的PC的癌细胞外部机制对DNA敏感性刺激具有抗药性 途径激活。第三，我们将询问直接的抗癌机制和治疗潜力 刺激性激动剂/PI3KI组合疗法在使PTEN-KNOCKOUT MURINE CRPC敏感为ICI中。总的来说，这些 “共同链接”研究将为下一波免疫治疗策略提供机械基础，以 根除PTEN LOF MCRPC。