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

项目摘要/摘要 研究：肺癌是美国癌症死亡的首要原因免疫的成功 使用PD-(L)1抗体进行检查点阻断是临床上的一个显著进展。然而， 大多数患者对ICB单一疗法没有反应，而大多数最初有反应的人最终有反应 死于这种疾病。恶性胸腔积液是一种具有挑战性的临床情景，与 预后差，对ICB治疗反应减退。本建议书中提供的初步数据表明 被激活的T细胞出人意料地表达磷脂酰丝氨酸，尽管仍具有活性和细胞毒性。此外， 磷脂酰丝氨酸的这种表达介导了腹膜对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的废除改善了 ICB对腹膜癌小鼠模型的反应。由于胸膜巨噬细胞的个体发育 在转录上与他们的腹膜巨噬细胞相似，我们假设Tim-4胸膜 巨噬细胞通过清除抗肿瘤CD8 T细胞在恶性胸腔积液中发挥免疫抑制作用。在……里面 在这项提议中，我们将系统地描述TIM-4巨噬细胞-PSHigh T细胞在两只小鼠中的相互作用 以及恶性胸腔积液的人体模型。此外，我们还将探讨TIM-4封锁是否具有 有可能大幅提高肺癌免疫疗法的疗效。 候选人：安德鲁·周博士是纪念斯隆大学医学系肿瘤学研究员 凯特琳癌症中心(MSKCC)。他的目标是成为一名独立的、终身教职的内科科学家 TIM-4胸膜巨噬细胞作为克服耐药性的新治疗靶点的研究 肺癌的免疫治疗。周博士将在戴维斯博士的指导下进行这项拟议的研究。 查尔斯·鲁丁和杰德·沃尔霍克是国际公认的肺癌和免疫疗法专家， 分别进行了分析。周博士概述了为期五年的指导性培训，这是在他的实验室基础上进行的 精通小鼠建模、流式细胞术和显微镜技术，并接受了内科肿瘤学的临床培训。对于 在下一阶段的指导培训中，他将发展单细胞RNA测序分析、CAR T细胞设计方面的技能 和制作、CRISPR-CAS9编辑和临床方案编写。周博士还组装了一口井- 由Sohrab Shah博士、Prasad Adusumilli博士和Katherine Panageas博士组成的成熟的咨询委员会， 他将帮助指导他的训练和研究。 环境：MSKCC是世界上最古老和最大的私人癌症中心，致力于130多年 出众的病人护理、创新的研究和出色的教育项目。MSKCC曝光受训人员 拥有非常强大的学术研究环境，并致力于 成功地支持正在寻求独立内科科学家职业生涯的初级教员。

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.