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

项目摘要 免疫疗法，特别是免疫检查点抑制剂（ICI），已经显示出相当大的成功， 晚期肾细胞癌（RCC）的治疗，导致患者亚组的持久反应。 然而，大多数患者并没有从现有的免疫疗法中获得长期的临床益处。移动 我们的团队已经优先确定RCC中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， 特异性免疫 人内源性逆转录病毒（ERV）通常在许多疾病状态中异常表达， 包括恶性肿瘤，并且可以导致先天免疫（通过RIG-I/MDA-5的感应）和免疫抑制剂（通过免疫抑制剂）的激活。 和cGAS-STING途径）和获得性免疫（通过为肿瘤特异性CD 8 + T细胞提供抗原靶点）。 细胞）。ERVE-4的表达与ICI单药治疗（即抗PD-1）的反应相关。 在RCC中进行的III期随机对照试验的分析中， 鉴定为对同种异体干细胞移植的长期RCC应答者中的靶表位。超出 为了识别肿瘤抗原，有效的抗肿瘤免疫需要肿瘤微环境， 浸润CD 8 + T细胞以执行其效应子功能。有大量的肿瘤被抗原浸润- 经验丰富的、未耗竭的CD 8 + T细胞与ICI单药治疗的应答改善相关。 RCC的临床试验。然而，对ICI单一疗法的耐药性仍然很常见，部分原因是 浸润性Treg和髓样细胞的免疫抑制作用，以及因此组合（而不是单一的） 目前，以PD-1阻断为骨干的抗肿瘤药物（如抗肿瘤药物）治疗是晚期RCC的标准治疗。 因此，理解ERV表达、T细胞表型和免疫调节的作用是至关重要的。 在临床相关的当代ICI为基础的组合疗法的背景下，微环境。 我们假设ERVs的异常表达与ICI的改善反应有关 使用伊匹单抗和纳武单抗的组合疗法，以及T细胞表型的表征和 RCC微环境中其他浸润免疫细胞的组成和状态将改善我们的免疫功能。 了解ICI反应的决定因素。通过利用我们独特的临床相关的大型- 单药ICI和基于ICI的RCC联合治疗的大规模临床试验样本，以及我们的 由医生，翻译研究人员和实验生物学家组成的合作团队，我们的目标是系统地 评估ERV表达和ICI反应的关联，并确定其他免疫微环境 这些特征最终影响对当前RCC免疫疗法的反应。我们的多学科团队 在RCC生物学，病理学和肿瘤免疫调节方面的集体专业知识，致力于 带来有意义的结果，将优化RCC患者的临床结局。

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.