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