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.

项目总结/摘要： 免疫检查点抑制剂（ICI）仅在10-25%的转移性去势抵抗性前列腺中有活性 癌症（mCRPC）患者。mCRPC中肿瘤微环境（TME）的协同临床免疫特征分析研究 患者和小鼠PC模型表现出稀疏的免疫浸润， 免疫抑制性骨髓细胞，特别是肿瘤相关巨噬细胞（TAM）。PTEN功能丧失 (LOF)发生在多种癌症中，特别是50-75%的mCRPC。它与预后不良有关， 多肿瘤临床前和临床研究中ICI的治疗结局和新发/获得性耐药 类型除了TAM在PC稀疏免疫浸润中占优势外，我们还观察到2倍的 相对于同基因PTEN-熟练的，在PTEN LOF TME内髓源性抑制细胞的增加 同行这些数据加强了我们的项目目标，即阐明改变的机制。 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抗性。 我们已经证明，环GMP-AMP合酶（c-GAS）/干扰素基因刺激因子（STING） 通常响应于胞质DNA双链断裂（DSB）而激活的信号通路， TME的髓样区室内的cGAS/STING活化对于产生肿瘤细胞的增殖是至关重要的。 强大的免疫浸润然而，DNA DSB的产生不足以增强T细胞浸润，这是不可能的。 与在我们的鼠模型和临床中观察到的对PARP抑制（PARPi）加ICI缺乏应答一致 问题研究更深入地探索这种断开，我们发现TAM中失败的STING通路激活 是这次抵抗的罪魁祸首此外，PI 3 K活性阻止了TAM中STING途径的激活， PI 3 K抑制（PI 3 Ki）加上PARPi的DNA损伤导致PTEN-proficient的ICI反应性，但不是 在同基因PTEN敲除PC中，提示其他免疫抑制机制由PTEN驱动， LOF。该建议的中心假设是，PTEN LOF PC对DNA DSB传感具有从头抗性 c-GAS/STING途径激活，这可以通过直接基于STING激动剂的组合来克服，导致 ICI敏感化。为了验证这一假设，我们提出了以下具体目标。首先，我们将解剖TME 在mCRPC患者中完成的PARPi/ICI的药物启动临床试验中， 在临床前模型中鉴定的免疫抑制机制与患者相关。第二，我们将阐明 PTEN缺陷型PC对DNA敏感STING重新产生抗性的癌细胞外在机制 通路激活第三，我们将探讨直接抗肿瘤的机制和治疗潜力， STING激动剂/PI 3 Ki组合疗法使PTEN敲除鼠CRPC对ICI敏感。总的来说，这些 “共同临床”研究将为下一波免疫策略提供机制基础， 根除PTEN LOF mCRPC。