Tissue-based biomarkers of anti-PD-1-based therapy in metastatic renal cell carcinoma

项目总结 免疫治疗，特别是免疫检查点抑制剂(ICI)，在 治疗晚期肾细胞癌(RCC)，导致部分患者出现持久反应。 然而，大多数患者并不能从现有的免疫疗法中获得长期的临床益处。搬家 展望未来，我们的团队已经优先确定肾细胞癌ICI反应的决定因素，包括抗原性 靶点、T细胞表型和微环境特征最终决定了肿瘤的有效性- 特定豁免权。 人类内源性逆转录病毒(ERV)通常在多种疾病状态下异常表达， 包括恶性肿瘤，并可导致两种天然免疫的激活(通过RIG-I/MDA-5的感应 和cGAS刺痛途径)和获得性免疫(通过为肿瘤特异性CD8+T细胞提供抗原靶点 单元格)。ERVE-4的表达与ICI单一治疗(即抗PD-1)的反应有关 肾细胞癌的III期随机对照试验分析，ERV衍生的多肽(来自ERVE-4) 被确认为RCC对异基因干细胞移植的长期应答者的目标表位。超越 识别肿瘤抗原，有效的抗肿瘤免疫需要肿瘤微环境 渗入CD8+T细胞，发挥其效应功能。抗原对肿瘤的高度浸润性- 有经验的、未耗尽的CD8+T细胞与ICI单一疗法的改善反应有关 肾细胞癌的临床试验。然而，对ICI单一疗法的耐药性仍然很普遍，部分原因是 浸润性Treg和髓系细胞及其联合的免疫抑制效应(而不是单一的 以PD-1阻断为主干的药物)治疗现在是晚期肾癌的标准治疗方法。 因此，了解ERV的表达、T细胞表型和免疫的作用至关重要。 与临床相关的当代ICI综合疗法背景下的微环境。 我们假设ERV的异常表达与ICI的反应增强有关 Ipilimumab和nivolumab联合治疗，以及T细胞表型和 肾癌微环境中其他浸润性免疫细胞的组成和状态将改善我们的 了解ICI反应的决定因素。通过利用我们独特的途径获得临床相关的大型- 肾细胞癌单药ICI和ICI联合治疗的规模临床试验标本，以及我们的 由医生、翻译研究人员和实验生物学家组成的协作团队，我们的目标是系统地 评估ERV表达与ICI反应的关系，并确定其他免疫微环境 最终影响对当前肾细胞癌免疫疗法反应的特征。我们的多学科团队带来了 汇集了肾细胞癌生物学、病理学和肿瘤免疫调节方面的专业知识，他们致力于 带来有意义的结果，将优化肾癌患者的临床结果。

PROJECT SUMMARY Immunotherapy, particularly immune checkpoint inhibitors (ICI), has shown considerable success in the treatment of advanced renal cell carcinoma (RCC), leading to durable responses in a subset of patients. However, most patients do not derive long-term clinical benefit from existing immune therapies. Moving forward, our team has prioritized identifying the determinants of ICI response in RCC, including the antigenic targets, T cell phenotypes, and microenvironment features that ultimately dictate the effectiveness of tumor- specific immunity. Human endogenous retroviruses (ERVs) are often aberrantly expressed in numerous disease states, including malignancy, and can lead to activation of both innate immunity (through sensing by the RIG-I/MDA-5 and cGAS-STING pathways) and adaptive immunity (by providing antigenic targets for tumor-specific CD8+ T cells). The expression of ERVE-4 has been associated with response to ICI monotherapy (i.e. anti-PD-1) in an analysis of a phase III randomized controlled trial in RCC, and an ERV-derived peptide (from ERVE-4) was identified as a target epitope in a long-term RCC responder to allogeneic stem cell transplant. Beyond recognition of tumor antigens, effective anti-tumor immunity requires a tumor microenvironment that permits infiltrating CD8+ T cells to carry out their effector function. A high level of tumor infiltration by antigen- experienced, non-exhausted CD8+ T cells has been associated with improved response to ICI monotherapy in clinical trials of RCC. However, resistance to ICI monotherapy is still common, in part owing to the immunosuppressive effects of infiltrating Treg and myeloid cells, and consequently combination (and not single agent) therapies with PD-1 blockade as a backbone are now the standard-of-care treatment for advanced RCC. It is therefore critical to understand the role of ERV expression, T cell phenotype, and the immune microenvironment in the context of clinically relevant contemporary ICI-based combination therapies. We hypothesize that aberrant expression of ERVs is associated with improved response to ICI combination therapy with ipilimumab and nivolumab, and that characterization of T cell phenotypes and the composition and states of other infiltrating immune cells in the RCC microenvironment will improve our understanding of the determinants of ICI response. By leveraging our unique access to clinically relevant large- scale clinical trial specimens of single-agent ICI and ICI-based combination therapy in RCC, as well as our collaborative team of physicians, translational researchers, and experimental biologists, we aim to systemically assess the association of ERV expression and ICI response and to determine other immune microenvironment features that ultimately influence response to current RCC immunotherapies. Our multidisciplinary team brings together a collective expertise in RCC biology, pathology, and tumor immunoregulation who are dedicated to bringing meaningful results that will optimize clinical outcomes for patients with RCC.