biostudies-literatureGaglia GNHLBI NIH HHSNCI NIH HHSNIGMS NIH HHS871-886.e10https://www.ebi.ac.uk/biostudies/studies/S-EPMC10193529biostudies-literatureUnknown41(5)Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1⁺ PD-1⁺ progenitCancer cellLymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma.PMC10193529T32 HL007627P30 CA006516R01 CA194005R41 CA224503P30 CA014051U54 CA225088K99 CA256497R50 CA274277U2C CA233262T32 GM007748Sorger PKCoy SCrossland GERammos DGaglia GWarchol SNirmal AJDai YKrueger RJaeger AMJacks TBurger MLPfister HSantagata STavana SZNaranjo SRitch CCLin JRfalseLymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma.Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1⁺ PD-1⁺ progenit2023-01-01T00:00:00Z2023 May2025-04-06T19:18:45.296Z2024-11-06T13:10:46.63ZS-EPMC101935293705910510.1016/j.ccell.2023.03.015