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、 刺激、抑制和以其他方式改变 T 细胞活性。因此需要检查多细胞组织组织 揭示 T 细胞抗肿瘤反应。然而，人们对多细胞网络的存在知之甚少。 癌症、它们的组织方式以及它们如何调节 T 细胞活性。该项目探讨了机械 候选人（乔纳森·陈博士）最近发现的肿瘤免疫多细胞网络（中心）的基础 人类结直肠癌的单细胞转录组研究。该提案的目的是调查 该免疫中枢的组成、空间组织和功能与抗肿瘤 T 细胞反应有关。 该提案旨在 (1) 空间绘制免疫中心中可能塑造 T 细胞行为的细胞相互作用 (2) 识别形成 CXCL13+ CD8 T 细胞状态的免疫中枢的环境因素，并揭示 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招募肿瘤特异性 T 细胞，并且中心内有多种细胞类型 参与塑造这些 T 细胞的状态。此外，对免疫中心的这项调查可能会 确定有前景的治疗操作策略。 候选人 Jonathan Chen 博士目前是 Nir ​​Hacohen 博士实验室的博士后，也是一名 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，包括超高重 RNA 分析培训 原位杂交数据集。结构化的职业发展计划包括培训和指导 实验室管理、科学领导、研究交流、资助写作和其他重要职业 技能。这些技术和职业技能将在 Nir ​​Hacohen 博士的指导下获得，他将在 作为主要导师，并有学员在学术界获得教职的历史，Eli Van Allen 博士 作为计算辅助导师。由包括博士在内的世界一流科学家组成的研究咨询委员会。阿琳 Sharpe、David Rimm 和 David Ting 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 过渡到独立的医师科学家教职职位，实验室专注于基本机制和 癌症免疫学的治疗机会。