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

Tim-4 胸膜巨噬细胞作为肺癌抗肿瘤 T 细胞免疫负调节因子的评估

• 批准号: 10437602
• 负责人: Andrew Chow
• 金额: $ 20.06万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437602
• 关键词: Advisory Committees; Anatomy; Antibodies; Antigens; Autoimmunity; CD8-Positive T-Lymphocytes; CRISPR/Cas technology; Cancer Center; Cancer Etiology; Cancer Model; Cancer Patient; Carcinomatosis; Cell Communication; Cessation of life; Clinical; Clinical Protocols; Coculture Techniques; Collaborations; Confocal Microscopy; Cytotoxic T-Lymphocytes; Data; Disease; Distant Metastasis; Environment; Faculty; Flow Cytometry; Functional disorder; Genetic; Genetic Transcription; Immunity; Immunosuppression; Immunotherapeutic agent; Immunotherapy; Impairment; International; Investigation; Laboratories; Life Expectancy; Link; Lung; Malignant Neoplasms; Malignant Pleural Effusion; Malignant neoplasm of lung; Mediating; Medical Oncology; Medicine; Memorial Sloan-Kettering Cancer Center; Mentors; Mentorship; Metastatic Neoplasm to the Liver; Microscopy; Modeling; Mus; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Patient Care; Patients; Peritoneal; Peritoneal Macrophages; Phagocytes; Phagocytosis; Phase; Phosphatidylserines; Physicians; Pleural; Pleural cavity; Positioning Attribute; Predisposition; Privatization; Prognosis; Research; Resistance; Role; Scientist; Specimen; T cell therapy; T-Lymphocyte; Testing; Therapeutic; Tissues; Training; Tumor Immunity; United States; Writing; anti-PD1 therapy; autoinflammatory; base; career; chimeric antigen receptor T cells; cytotoxic; cytotoxic CD8 T cells; design; experience; human model; immune checkpoint blockade; improved; in vivo; innovation; macrophage; mesothelin; mouse model; neoplastic cell; new therapeutic target; novel strategies; phosphatidylserine receptor; programs; response; secondary lymphoid organ; single-cell RNA sequencing; skills; success; tenure track; tumor; tumor-immune system interactions

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.

项目总结/摘要 研究：肺癌是美国癌症死亡的主要原因。免疫的成功 使用PD-（L）1抗体的检查点阻断（ICB）已经是显著的临床进展。但 大多数患者对ICB单药治疗无反应，大多数最初有反应的患者最终有反应 死于疾病恶性胸腔积液是一种具有挑战性的临床情况， 预后差对ICB的反应也低本提案中提供的初步数据表明， 活化的T细胞令人惊讶地表达磷脂酰丝氨酸，尽管仍保持活力和细胞毒性。此外，委员会认为， 磷脂酰丝氨酸的这种表达介导了对腹膜巨噬细胞吞噬清除的敏感性， 表达磷脂酰丝氨酸受体Tim-4的巨噬细胞。此外，Tim-4废除改善了 在腹膜癌病的小鼠模型中对ICB的反应。由于胸膜巨噬细胞在个体发育上 并且在转录上与它们的腹腔巨噬细胞对应物相似，我们假设Tim-4+胸膜炎细胞可能是一种免疫抑制剂。 巨噬细胞通过清除抗肿瘤CD 8 + T细胞在恶性胸腔积液中赋予免疫抑制。在 在本研究中，我们将系统地描述Tim-4+巨噬细胞-PS高T细胞相互作用， 和恶性胸腔积液的人类模型。此外，我们将探讨蒂姆-4封锁是否具有 这可能大大提高肺癌免疫治疗的疗效。 候选人：Andrew Chow博士是纪念斯隆医学系的医学肿瘤学研究员 凯特林癌症中心（MSKCC）。他的目标是成为一名独立的、终身教职的物理学家兼科学家 研究Tim-4+胸膜巨噬细胞作为新的治疗靶点以克服对 肺癌的免疫治疗周博士将在周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，建立在他的实验室为基础的 他在小鼠建模、流式细胞术和显微镜方面的技能以及他在医学肿瘤学方面的临床培训。为 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 和生产，CRISPR-Cas9编辑和临床方案编写。周博士还组织了一个很好的- 由Sohrab Shah、Prasad Adusumilli和凯瑟琳Panageas博士组成的咨询委员会， 指导他的训练和研究 环境：MSKCC是世界上历史最悠久，规模最大的私人癌症中心，致力于130多年来， 卓越的患者护理、创新的研究和出色的教育计划。MSKCC暴露学员 一个非常强大的学术研究环境，具有坚定的承诺和跟踪记录， 成功地支持年轻的教师谁正在寻求职业生涯作为独立的物理学家，科学家。

项目成果

Insights from prospective multi-omic profiling of lymphocytes in resected lung cancer.

• DOI: 10.1016/j.annonc.2021.10.013
• 发表时间: 2021-10
• 期刊: Annals of oncology : official journal of the European Society for Medical Oncology
• 作者: A. Chow;M. Hellmann

Spontaneous Bilateral Chylothorax Development During Alectinib Therapy for ALK-Rearranged NSCLC-A Case Report.

• DOI: 10.1016/j.jtocrr.2023.100606
• 发表时间: 2023-12
• 期刊: JTO CLINICAL AND RESEARCH REPORTS
• 作者: Bajaj, Sunanjay;Chow, Andrew;Drilon, Alexander;Kalchiem-Dekel, Or
• 通讯作者: Kalchiem-Dekel, Or