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细胞受到环境的极大影响，与可能吸引的邻近细胞相互作用， 刺激、抑制或改变T细胞活性。因此，检查多细胞组织组织是必要的 来解开T细胞抗肿瘤的反应。然而，人们对多蜂窝网络的存在知之甚少。 癌症，它们是如何组织的，以及它们是如何调节T细胞活动的。这个项目探索的是 候选人(乔纳森·陈博士)最近发现的肿瘤免疫多细胞网络(HUB)的基础 人结直肠癌的单细胞转录研究。这项建议的目的是调查 这个免疫中枢的组成、空间组织和功能与抗肿瘤T细胞反应有关。 这一建议旨在(1)绘制免疫中枢中可能塑造T细胞行为的细胞相互作用的空间图谱 以及(2)识别形成CXCL13+CD8 T细胞状态的免疫中枢中的环境因素，并揭示 CXCL13在结直肠癌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招募肿瘤特异性T细胞，中枢内多种细胞类型 参与塑造这些T细胞的状态。此外，对免疫中心的调查很可能会 确定治疗操作的有前景的策略。 候选人乔纳森·陈博士目前是尼尔·哈科恩博士实验室的博士后， 麻省总医院病理科讲师。该提案包含了 项目所需的具体技术技能，包括超高拷贝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、研究沟通、拨款撰写等关键职业 技能。这些技术和职业技能将在尼尔·哈科恩博士的指导下获得，他将在 作为主要导师，并有受训人员在学术界获得教职的历史，以及Eli Van Allen博士 作为计算方面的共同导师。由包括Arlene博士在内的世界级科学家组成的研究咨询委员会 Sharpe、David Rimm和David Ting将提供额外的支持和指导。通过这件事 综合计划，候选人将获得一套独特的研究技能，使他能够 过渡到独立的医生-科学家教职员工职位，实验室专注于基本机制和 癌症免疫学中的治疗机会。