Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy

期刊论文
发表日期：

2024年3月19日

查看全文

Jonathan H. Chen,
Linda T. Nieman,
Maxwell Spurrell,
Vjola Jorgji,
Liad Elmelech,
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 J. Aryee,
Mari Mino-Kenudson,
Justin F. Gainor,
Ilya Korsunsky,
Nir Hacohen

摘要

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 an association with beneficial response to PD-1 blockade. Critically, we discovered the stem-immunity hub, a subtype of immunity hub strongly associated with favorable PD-1-blockade outcome. This hub is distinct from mature tertiary lymphoid structures and is enriched for stem-like TCF7⁺PD-1⁺CD8⁺ T cells, activated CCR7⁺LAMP3⁺ dendritic cells and CCL19⁺ fibroblasts as well as chemokines that organize these cells. Within the stem-immunity hub, we find preferential interactions between CXCL10⁺ macrophages and TCF7⁻CD8⁺ T cells as well as between mature regulatory dendritic cells and TCF7⁺CD4⁺ and regulatory T cells. These results provide a picture of the spatial organization of the human intratumoral immune response and its relevance to patient immunotherapy outcomes.