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.
Competing Interest Statement
C.S.N. holds equity in Opko Health and receives royalties from Life Technologies and Cambridge Epigenetix. S.F.'s salary is partially supported by research funding from IBM. A.M. has served a consultant/advisory role for Third Rock Ventures, Asher Biotherapeutics, Abata Therapeutics, Flare Therapeutics, venBio Partners, BioNTech, Rheos Medicines and Checkmate Pharmaceuticals, is an equity holder in Asher Biotherapeutics and Abata Therapeutics, and has a sponsored research agreement with Bristol-Myers Squibb and Olink Proteomics. M.S.-F. receives funding from Bristol-Myers Squibb. G.M.B. has sponsored research agreements with Olink Proteomics, InterVenn, Palleon Pharmaceuticals, and Takeda Oncology, has served as a consultant for Merck, Ankyra Therapeutics, and InterVenn, and is a scientific advisory board member for Iovance, Merck, Ankyra Therapeutics, and InstilBio. M.A. has a financial interest in SeQure Dx, Inc. M.M.-K. has served as a consultant for AstraZeneca, BMS, Sanofi, and Janssen Oncology and receives royalties from Elsevier. J.F.G. has consulted and/or had advisory roles for Agios, Amgen, AstraZeneca, Array BioPharma, Blueprint Medicines Corporation, BMS, Genentech/Roche, Gilead Sciences, Jounce Therapeutics, Lilly, Loxo Oncology, Merck, Mirati, Silverback Therapeutics, Sanofi, GlydeBio, Curie Therapeutics, Novartis, Moderna Therapeutics, Oncorus, Regeneron, Takeda, Pfizer; has stock and ownership in Ironwood Pharmaceuticals; and has received Honoraria from Merck, Novartis, Pfizer, and Takeda; and institutional research funding from Adaptimmune, ALX Oncology, Merck, Array BioPharma, AstraZeneca, Blueprint Medicines Corporation, BMS, Scholar Rock, Genentech, Jounce Therapeutics, Merck, Novartis; research funding from Novartis, Genentech/Roche, and Takeda, has an immediate family member who is an employee of Ironwood Pharmaceuticals. N.H. holds equity in BioNTech and is an advisor for Related Sciences/Danger Bio. J.H., N.F.F., and G.E. are employees of Vizgen, Inc. C.P. (now at Takeda) was an employee of Vizgen when this research was conducted. J.W.R. and K.V.R. are employees of NanoString, Inc. I.K. receives research funding from the Chan Zuckerberg Initiative and has consulting/advisory roles with Mestag Therapeutics Ltd and Scailtye AG.
