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Spatial analysis of human lung cancer reveals organized immune hubs enriched for stem-like CD8 T cells and associated with immunotherapy response

Jonathan H Chen et al. bioRxiv. .

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  • Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy.
    Chen JH, Nieman LT, Spurrell M, Jorgji V, Elmelech L, Richieri P, Xu KH, Madhu R, Parikh M, Zamora I, Mehta A, Nabel CS, Freeman SS, Pirl JD, Lu C, Meador CB, Barth JL, Sakhi M, Tang AL, Sarkizova S, Price C, Fernandez NF, Emanuel G, He J, Van Raay K, Reeves JW, Yizhak K, Hofree M, Shih A, Sade-Feldman M, Boland GM, Pelka K, Aryee MJ, Mino-Kenudson M, Gainor JF, Korsunsky I, Hacohen N. Chen JH, et al. Nat Immunol. 2024 Apr;25(4):644-658. doi: 10.1038/s41590-024-01792-2. Epub 2024 Mar 19. Nat Immunol. 2024. PMID: 38503922 Free PMC article.

Abstract

The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially-localized multicellular 'immunity hubs' defined by expression of the T cell-attracting chemokines CXCL10/CXCL11 and abundant T cells. Here, we examined immunity hubs in human pre-immunotherapy lung cancer specimens, and found that they were associated with beneficial responses to PD-1-blockade. Immunity hubs were enriched for many interferon-stimulated genes, T cells in multiple differentiation states, and CXCL9/10/11 + macrophages that preferentially interact with CD8 T cells. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcomes, distinct from mature tertiary lymphoid structures, and enriched for stem-like TCF7+PD-1+ CD8 T cells and activated CCR7 + LAMP3 + dendritic cells, as well as chemokines that organize these cells. These results elucidate the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.

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