Assessment of Tim-4+ Pleural Macrophages as Negative Regulators of Anti-Tumor T Cell Immunity in Lung Cancer

项目概要/摘要 研究：肺癌是美国癌症死亡的主要原因。免疫成功 使用 PD-(L)1 抗体进行检查点阻断 (ICB) 是一项显着的临床进展。然而， 大多数患者对 ICB 单一疗法没有反应，大多数最初有反应的患者最终有反应 屈服于疾病。恶性胸腔积液是一种具有挑战性的临床情况，与 预后不良且对 ICB 的反应降低。本提案中提供的初步数据表明 激活的 T 细胞令人惊讶地表达磷脂酰丝氨酸，尽管仍然保持活力和细胞毒性。而且， 磷脂酰丝氨酸的这种表达介导腹膜吞噬细胞清除的易感性 表达磷脂酰丝氨酸受体 Tim-4 的巨噬细胞。此外，Tim-4废除改进了 腹膜癌病小鼠模型对 ICB 的反应。由于胸膜巨噬细胞是个体发育的 并且在转录上与腹膜巨噬细胞相似，我们假设 Tim-4 胸膜巨噬细胞 巨噬细胞通过清除抗肿瘤 CD8 T 细胞对恶性胸腔积液产生免疫抑制。在 在此提案中，我们将系统地表征小鼠体内 Tim-4 巨噬细胞与 PShigh T 细胞的相互作用 以及恶性胸腔积液的人体模型。此外，我们将探讨 Tim-4 封锁是否具有 显着增强肺癌免疫疗法疗效的潜力。 候选人：Andrew Chow 博士是纪念斯隆管理学院医学系肿瘤内科研究员 凯特林癌症中心 (MSKCC)。他的目标是成为一名独立的终身教授医师科学家 研究 Tim-4 胸膜巨噬细胞作为克服耐药性的新治疗靶点 肺癌的免疫疗法。周博士将在博士的指导下进行拟议的研究。 Charles Rudin 和 Jedd Wolchok 是国际公认的肺癌和免疫治疗专家， 分别。周博士概述了一个为期五年的指导培训，该培训以他的实验室为基础 他在小鼠建模、流式细胞术和显微镜方面的技能以及他在肿瘤医学方面的临床培训。对于 在下一阶段的指导培训中，他将培养单细胞 RNA 测序分析、CAR T 细胞设计方面的技能 和制造、CRISPR-Cas9 编辑和临床方案编写。周博士还组建了一套完善的 卓有成效的顾问委员会由博士组成。索拉博·沙阿、普拉萨德·阿杜苏米利和凯瑟琳·帕纳盖斯， 谁将帮助指导他的培训和研究。 环境：MSKCC 是世界上历史最悠久、规模最大的私立癌症中心，130 多年来致力于 卓越的患者护理、创新的研究和出色的教育计划。 MSKCC曝光练习生 一个异常强大的学术研究环境，具有坚定的承诺和跟踪记录 成功地支持寻求独立医师科学家职业的初级教师。

PROJECT SUMMARY/ABSTRACT Research: Lung cancer is the leading cause of cancer death in the United States. The success of immune checkpoint blockade (ICB) with antibodies to PD-(L)1 have been a remarkable clinical advance. However, the majority of patients do not respond to ICB monotherapy and most of those who initially do respond eventually succumb to the disease. Malignant pleural effusions represent a challenging clinical scenario that is associated with poor prognosis and reduced responses to ICB. Preliminary data presented in this proposal demonstrates that activated T cells surprisingly express phosphatidylserine despite remaining viable and cytotoxic. Moreover, this expression of phosphatidylserine mediates susceptibility to phagocytic clearance by peritoneal macrophages that express the phosphatidylserine receptor Tim-4. In addition, Tim-4 abrogation improves responses to ICB in a murine model of peritoneal carcinomatosis. As pleural macrophages are ontogenically and transcriptionally similar to their peritoneal macrophage counterpart, we hypothesize that Tim-4+ pleural macrophages impart immunosuppression in malignant pleural effusions by clearing anti-tumor CD8+ T cells. In this proposal, we will systematically characterize Tim-4+ macrophage-PShigh T cell interactions in both murine and human models of malignant pleural effusion. Furthermore, we will explore whether Tim-4 blockade has the potential to substantially enhance the efficacy of immunotherapy in lung cancer. Candidate: Dr. Andrew Chow is a Medical Oncology Fellow in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSKCC). He aims to become an independent, tenure-track physician-scientist investigating Tim-4+ pleural macrophages as a novel therapeutic target to overcome resistance to immunotherapies in lung cancer. Dr. Chow will conduct the proposed research under the mentorship of Drs. Charles Rudin and Jedd Wolchok, who are internationally recognized experts in lung cancer and immunotherapy, respectively. Dr. Chow has outlined a five-year period of mentored training that builds on his laboratory-based skills in mouse modeling, flow cytometry, and microscopy and his clinical training in medical oncology. For the next phase of mentored training, he will develop skills in single-cell RNA sequencing analysis, CAR T cell design and manufacture, CRISPR-Cas9 editing, and clinical protocol writing. Dr. Chow has also assembled a well- accomplished advisory committee composed of Drs. Sohrab Shah, Prasad Adusumilli, and Katherine Panageas, who will help to guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.