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.

Grant Number: 5K08CA273547-03
NIH Institute/Center: NIH
Principal Investigator: Jonathan Chen