Elucidating the molecular and cellular mechanisms of immune evasion in pancreatic cancer

阐明胰腺癌免疫逃避的分子和细胞机制

• 批准号: 10646247
• 负责人: WILLIAM A FREED-PASTOR
• 金额: $ 21.13万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646247
• 关键词: Acceleration; Adaptive Immune System; Adopted; Animals; Award; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Biology; Cell Compartmentation; Cell physiology; Cells; Clinical; Clinical Trials; Combination immunotherapy; Cytotoxic T-Lymphocytes; Dana-Farber Cancer Institute; Development; Digit structure; Disease; Effectiveness; Evaluation; Flow Cytometry; Functional disorder; Goals; Heterogeneity; Histopathology; Human; Immune; Immune Evasion; Immune Targeting; Immune response; Immune system; Immunofluorescence Immunologic; Immunologic Surveillance; Immunotherapy; International; Lead; Malignant Neoplasms; Malignant neoplasm of pancreas; Mentors; Mentorship; Modeling; Molecular; Mus; Myelogenous; Myeloid-derived suppressor cells; Pancreatic Adenocarcinoma; Pancreatic Ductal Adenocarcinoma; Patients; Phenotype; Pre-Clinical Model; Prognosis; Proteome; Public Health; Research; Research Personnel; Resected; Resistance; Resolution; Resources; Sampling; Specificity; Survival Rate; T cell infiltration; T cell response; T-Lymphocyte; TNFRSF5 gene; Techniques; Technology; Therapeutic; Time; Training Programs; Tumor-Infiltrating Lymphocytes; Work; anti-tumor immune response; anticancer research; cancer cell; cancer immunotherapy; career; combat; exhaustion; experience; granulocyte; imaging modality; immune clearance; improved; improved outcome; insight; interest; multiplexed imaging; neoantigens; pancreatic cancer patients; pre-clinical; prevent; programmed cell death protein 1; resistance mechanism; response; single-cell RNA sequencing; spatiotemporal; therapeutically effective; transcriptomics; tumor; tumor immunology; tumor microenvironment; tumor progression; tumor-immune system interactions; tumorigenesis

PROJECT SUMMARY/ABSTRACT Pancreatic adenocarcinoma (PDAC) carries a dismal prognosis and remains a critical unmet public health need. The recent recognition that a subset of pancreas cancer harbors potential neoantigens has intensified interest in defining the molecular and cellular mechanisms of immune evasion in PDAC to guide effective therapeutic strategies that leverage the adaptive immune system in this disease. However, difficulty in precisely defining the tumor-reactive T cell compartment has hampered prior efforts to delineate the full spectrum of mechanisms by which PDAC evades immune eradication. I hypothesize that a subset of PDAC escapes immune surveillance through dysfunction and/or altered localization of tumor-reactive T cells. Our preliminary studies, using neoantigen-expressing preclinical models of PDAC to evaluate tumor-specific immune responses, have revealed that a significant subset of tumors acquire the ability to evade immune clearance and that neoantigen-specific cos• tumor-infiltrating lymphocytes (TILs) adopt multiple states of dysfunction. Additionally, we recently demonstrated that the CD155/TIGIT axis both promotes and maintains immune evasion in PDAC (Freed-Pastor et al. Cancer Cell, in press). In this proposal, I leverage recently developed preclinical models, advances in single-cell profiling, and highly multiplexed imaging modalities to interrogate the cytotoxic T cell compartment in murine and human PDAC. Specifically, I will evaluate the effects of TIGIT/PD-1 co-blockade plus CD40 agonism on the tumor-immune microenvironment in PDAC using single-cell transcriptomic and highly multiplexed immunofluorescence technologies. I will also utilize flow cytometry and multiplexed imaging to investigate the spatiotemporal dynamics of T cell phenotypes and localization during tumor progression in preclinical models, and compare T cell responses to different neoantigens. Furthermore, I will perform high-resolution profiling on TILs isolated directly from pancreas cancer patients. Collectively, these studies hold tremendous promise for accelerating effective immune-based therapies for PDAC. The proposed research will be performed at the Koch Institute for Integrative Cancer Research at MIT, under the guidance of Dr. Tyler Jacks, an international leader in cancer biology and tumor immunology, with co-mentorship by Dr. Brian Wolpin, a leading pancreas cancer researcher at the Dana-Farber Cancer Institute. Importantly, this research strategy is one part of a comprehensive training program to support my transition to an independent research career in basic and translational cancer biology and tumor immunology. My scientific advisors (Drs. Arlene Sharpe, Stefani Spranger, and Osama Rahma) are distinguished experts with experience highly relevant to the proposed research. My long-term goal is to lead an independent academic research group, focused on deciphering the molecular and cellular mechanisms by which PDAC evades immune clearance, such that these insights can be used to guide therapeutic strategies to combat pancreas cancer and other cancers. The K08 award will provide pivotal protected time for continued mentored research and enable a successful transition to independence.

项目概要/摘要 胰腺癌（PDAC）的预后很差，并且仍然是一个未得到满足的重要公共卫生需求。最近认识到胰腺癌的一个亚型含有潜在的新抗原，这增强了人们对定义 PDAC 免疫逃避的分子和细胞机制的兴趣，以指导在这种疾病中利用适应性免疫系统的有效治疗策略。然而，精确定义肿瘤反应性 T 细胞区室的困难阻碍了先前描述 PDAC 逃避免疫根除的全部机制的努力。我假设 PDAC 的一个子集通过功能障碍和/或改变肿瘤反应性 T 细胞的定位来逃避免疫监视。我们的初步研究使用表达新抗原的 PDAC 临床前模型来评估肿瘤特异性免疫反应，结果表明，很大一部分肿瘤获得了逃避免疫清除的能力，并且新抗原特异性 cos• 肿瘤浸润淋巴细胞 (TIL) 呈现多种功能障碍状态。此外，我们最近证明 CD155/TIGIT 轴既促进又维持 PDAC 中的免疫逃避（Freed-Pastor 等人，Cancer Cell，出版中）。在本提案中，我利用最近开发的临床前模型、单细胞分析的进展以及高度多重成像模式来研究小鼠和人类 PDAC 中的细胞毒性 T 细胞区室。具体来说，我将使用单细胞转录组学和高度多重免疫荧光技术评估 TIGIT/PD-1 共同阻断加上 CD40 激动对 PDAC 中肿瘤免疫微环境的影响。我还将利用流式细胞术和多重成像来研究临床前模型中肿瘤进展过程中 T 细胞表型和定位的时空动态，并比较 T 细胞对不同新抗原的反应。此外，我将对直接从胰腺癌患者中分离的 TIL 进行高分辨率分析。总的来说，这些研究为加速 PDAC 的有效免疫疗法带来了巨大希望。拟议的研究将在癌症生物学和肿瘤免疫学领域的国际领导者 Tyler Jacks 博士的指导下，在麻省理工学院的科赫综合癌症研究所进行，并由丹纳法伯癌症研究所领先的胰腺癌研究员 Brian Wolpin 博士共同指导。重要的是，这项研究策略是综合培训计划的一部分，以支持我过渡到基础和转化癌症生物学和肿瘤免疫学的独立研究职业。我的科学顾问（Arlene Sharpe 博士、Stefani Spranger 和 Osama Rahma）是杰出的专家，他们的经验与拟议的研究高度相关。我的长期目标是领导一个独立的学术研究小组，专注于破译 PDAC 逃避免疫清除的分子和细胞机制，以便这些见解可用于指导对抗胰腺癌和其他癌症的治疗策略。 K08 奖项将为继续指导研究提供关键的受保护时间，并实现向独立的成功过渡。