Delineating the mechanisms by which tumor immunity multicellular networks shape T cell state

描述肿瘤免疫多细胞网络塑造 T 细胞状态的机制

• 批准号: 10662688
• 负责人: Jonathan Howard Chen
• 金额: $ 22.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10662688
• 关键词: Academia; Advisory Committees; Antigens; Antitumor Response; Area; B-Lymphocytes; Behavior; Biological; Biological Assay; Biology; Blood Vessels; CD8-Positive T-Lymphocytes; CXCL10 gene; CXCL11 gene; CXCL13 gene; Cancer Patient; Cell Communication; Cells; Chronic; Colorectal Cancer; Communication; Data; Data Set; Development Plans; Environment; Environmental Risk Factor; Faculty; Feedback; General Hospitals; Genes; Grant; Human; Hybrids; Hypoxia; Immune; Immunity; Immunotherapy; In Situ Hybridization; Interferon Type II; Interferons; Investigation; Laboratories; Leadership; Ligands; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Massachusetts; Mentors; Mentorship; Microscopy; Mismatch Repair; Mismatch Repair Deficiency; Molds; Morphology; Neighborhoods; PD-1 blockade; Pathologist; Pathology; Pathway interactions; Patients; Phenotype; Physicians; Population; Positioning Attribute; Postdoctoral Fellow; Process; Professional Competence; RNA; Recording of previous events; Recurrence; Research; Research Proposals; Role; Sampling; Scientist; Series; Shapes; Specimen; Structure; T cell response; T-Cell Activation; T-Cell Proliferation; T-Lymphocyte; Technical Expertise; Therapeutic; Tissues; Training; Tumor Immunity; Writing; anti-tumor immune response; cancer cell; cancer therapy; career development; cell behavior; cell type; chemokine; clinically significant; combat; exhaust; exhaustion; fighting; human DNA; improved; in vitro testing; instructor; lymph nodes; programs; recruit; response; skills; stem; transcriptomics; translational potential; tumor; tumor immunology

T cells are greatly impacted by their environment, interacting with neighboring cells that may attract, stimulate, inhibit, and otherwise alter T cell activity. Examining multicellular tissue organization is thus required for unraveling the T cell anti-tumor response. Yet, little is known about what multicellular networks exist in cancer, how they are organized, and how they modulate T cell activity. This project explores the mechanistic basis of a tumor immunity multicellular network (hub) discovered in the candidate’s (Dr. Jonathan Chen) recent single cell transcriptomic study of human colorectal cancer. The objective of this proposal is to investigate the composition, spatial organization and function of this immunity hub in relation to the anti-tumor T cell response. This proposal aims to (1) spatially map cellular interactions in the immunity hub that may shape T cell behavior and (2) identify environmental factors in the immunity hub shaping CXCL13+ CD8 T cell state and uncover the role of CXCL13 in CRC. The candidate anticipates these studies will demonstrate that the newly discovered tumor immunity multicellular network recruits tumor-specific T cells, and that multiple cell types within the hub participate in shaping the state of these T cells. Furthermore, this investigation of the immunity hub is likely to identify promising strategies for therapeutic manipulation. The candidate, Dr. Jonathan Chen, is currently a postdoc in the lab of Dr. Nir Hacohen and an Instructor in the Department of Pathology of the Massachusetts General Hospital. The proposal incorporates specific technical skills that will be required for the project, including training in analysis of ultra-highplex RNA in situ hybridization datasets. The structured career development plan includes training and mentorship in laboratory management, scientific leadership, research communication, grant writing, and other critical career skills. These technical and career skills will be acquired under the guidance of Dr. Nir Hacohen, who will serve as primary mentor and has a history of trainees obtaining faculty positions in academia, and Dr. Eli Van Allen as computational co-mentor. A Research Advisory Committee of world-class scientists including Drs. Arlene Sharpe, David Rimm, and David Ting will provide additional support and guidance. Through this comprehensive program, the candidate will acquire a unique set of research skills that will enable him to transition to an independent physician-scientist faculty position with a lab focused on basic mechanisms and therapeutic opportunities in cancer immunology.

T细胞受其环境的影响很大，与邻近细胞相互作用， 刺激、抑制和改变T细胞活性。因此需要检查多细胞组织结构 来解释T细胞的抗肿瘤反应然而，人们对多细胞网络存在于什么样的环境中知之甚少。 癌症，它们是如何组织的，以及它们如何调节T细胞活性。这个项目探讨了机械的 肿瘤免疫多细胞网络（枢纽）的基础上发现的候选人（博士乔纳森陈）最近 人结直肠癌单细胞转录组学研究本提案的目的是调查 本发明涉及与抗肿瘤T细胞应答相关的该免疫枢纽的组成、空间组织和功能。 该提案旨在（1）在免疫中枢中空间映射可能塑造T细胞行为的细胞相互作用 和（2）鉴定形成CXCL 13 + CD8 T细胞状态的免疫中枢中的环境因素，并揭示免疫中枢中的环境因素。 CXCL13在CRC中的作用候选人预计这些研究将证明，新发现的 肿瘤免疫多细胞网络募集肿瘤特异性T细胞，并且枢纽内的多种细胞类型 参与塑造这些T细胞的状态。此外，这次对免疫中心的调查很可能 确定有希望的治疗策略。 候选人Jonathan Chen博士目前是Nir Hacohen博士实验室的博士后， 马萨诸塞州总医院病理科讲师。该提案包括 该项目所需的具体技术技能，包括超高链RNA分析方面的培训 原位杂交数据集。结构化的职业发展计划包括以下方面的培训和指导： 实验室管理、科学领导、研究交流、资助写作和其他重要职业 skills.这些技术和职业技能将在Nir Hacohen博士的指导下获得， 作为主要导师，并有学员获得学术界教职的历史，和博士伊莱货车艾伦 作为计算导师包括阿琳博士在内的世界级科学家组成的研究咨询委员会 夏普、大卫里姆和大卫廷将提供额外的支持和指导。通过这个 综合计划，候选人将获得一套独特的研究技能，使他能够 过渡到一个独立的物理学家，科学家教师的立场与实验室侧重于基本机制， 癌症免疫学的治疗机会。