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, Linda T. Nieman, Maxwell Spurrell, Vjola Jorgji, Peter Richieri, Katherine H. Xu, Roopa Madhu, Milan Parikh, Izabella Zamora, Arnav Mehta, Christopher S. Nabel, Samuel S. Freeman, Joshua D. Pirl, Chenyue Lu, Catherine B. Meador, Jaimie L. Barth, Mustafa Sakhi, Alexander L. Tang, Siranush Sarkizova, Colles Price, Nicolas F. Fernandez, George Emanuel, Jiang He, Katrina Van Raay, Jason W. Reeves, Keren Yizhak, Matan Hofree, Angela Shih, Moshe Sade-Feldman, Genevieve M. Boland, Karin Pelka, Martin Aryee, Ilya Korsunsky, Mari Mino-Kenudson, Justin F. Gainor, Nir Hacohen
bioRxiv (2023)


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.