Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy.
Jonathan H ChenLinda T NiemanMaxwell SpurrellVjola JorgjiLiad ElmelechPeter RichieriKatherine H XuRoopa MadhuMilan ParikhIzabella ZamoraArnav MehtaChristopher S NabelSamuel S FreemanJoshua D PirlChenyue LuCatherine B MeadorJaimie L BarthMustafa SakhiAlexander L TangSiranush SarkizovaColles PriceNicolas F FernandezGeorge EmanuelJiang HeKatrina Van RaayJason W ReevesKeren YizhakMatan HofreeAngela R ShihMoshe Sade-FeldmanGenevieve Marie BolandKarin PelkaMartin J AryeeMari A Mino-KenudsonJustin F GainorIlya KorsunskyNir HacohenPublished in: Nature immunology (2024)
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.