Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma

Cancer Cell. 2023 May 8;41(5):871-886.e10. doi: 10.1016/j.ccell.2023.03.015. Epub 2023 Apr 13.


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+ progenitor CD8+ T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained 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.

Keywords: CyCIF; cancer vaccines; computational biology; immunotherapy; lung adenocarcinoma; multimodal data integration; multiplexed imaging; spatial biology; spatial profiling; systems biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma of Lung* / genetics
  • Animals
  • CD8-Positive T-Lymphocytes
  • Humans
  • Immunity
  • Immunotherapy / methods
  • Lung Neoplasms* / pathology
  • Mice