PT - JOURNAL ARTICLE AU - Giorgio Gaglia AU - Megan L. Burger AU - Cecily C. Ritch AU - Danae Rammos AU - Yang Dai AU - Grace E. Crossland AU - Sara Z. Tavana AU - Simon Warchol AU - Alex M. Jaeger AU - Santiago Naranjo AU - Shannon Coy AU - Ajit J. Nirmal AU - Robert Krueger AU - Jia-Ren Lin AU - Hanspeter Pfister AU - Peter K Sorger AU - Tyler Jacks AU - Sandro Santagata TI - Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma AID - 10.1101/2022.08.11.503237 DP - 2022 Jan 01 TA - bioRxiv PG - 2022.08.11.503237 4099 - http://biorxiv.org/content/early/2022/08/13/2022.08.11.503237.short 4100 - http://biorxiv.org/content/early/2022/08/13/2022.08.11.503237.full AB - Lymphocytes play a key role in immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. Here, we used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of tumor-bearing lung tissues from a Kras/p53 (KP) mouse model and human resections. Networks of directly interacting lymphocytes (‘lymphonets’) emerge as a distinctive feature of the anti-cancer immune response. Lymphonets nucleate from small T-cell clusters and incorporate B cells with increasing size. CXCR3-mediated trafficking modulates lymphonet size and number, but neoantigen expression directs intratumoral localization. Lymphonets preferentially harbor TCF1+/PD1+ progenitor CD8 T cells involved in responses to immune checkpoint blockade (ICB). Upon treatment of mice with ICB therapy or a neoantigen-targeted vaccine, lymphonets retain progenitor and gain cytotoxic CD8 T-cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8 T-cell anti-tumor responses.Competing Interest StatementPKS is a member of BOD of Applied Biomath, RareCyte Inc., and Glencoe Software, in which he is also a cofounder; Glencoe Software distributes a commercial version of the OMERO image informatics software used in this paper; PKS is a member of the SAB for NanoString and Montai Health and a consultant for Merck. In the last five years the Sorger lab has received research funding from Novartis and Merck. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific and a co-founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. is also President of Break Through Cancer. T.J. laboratory currently receives funding from the Johnson & Johnson Lung Cancer Initiative and The Lustgarten Foundation for Pancreatic Cancer Research, but this funding did not support the research described in the manuscript. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this manuscript. Other authors declare no competing interests.