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

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

doi:10.1038/s41590-024-01792-2

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

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 SarkizovaColles 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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

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 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.

Original language	English
Pages (from-to)	644-658
Number of pages	15
Journal	Nature Immunology
Volume	25
Issue number	4
DOIs	https://doi.org/10.1038/s41590-024-01792-2
State	Published - Apr 2024

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Publisher Copyright:
© The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.

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Chen, J. H., Nieman, L. T., Spurrell, M., Jorgji, V., Elmelech, L., Richieri, P., Xu, K. H., Madhu, R., Parikh, M., Zamora, I., Mehta, A., Nabel, C. S., Freeman, S. S., Pirl, J. D., Lu, C., Meador, C. B., Barth, J. L., Sakhi, M., Tang, A. L., ... Hacohen, N. (2024). Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy. Nature Immunology, 25(4), 644-658. https://doi.org/10.1038/s41590-024-01792-2

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title = "Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy",

abstract = "The organization of immune cells in human tumors is not well understood. Immunogenic tumors harbor spatially localized multicellular {\textquoteleft}immunity hubs{\textquoteright} 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.",

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

note = "Publisher Copyright: {\textcopyright} The Author(s), under exclusive licence to Springer Nature America, Inc. 2024.",

year = "2024",

month = apr,

doi = "10.1038/s41590-024-01792-2",

language = "אנגלית",

volume = "25",

pages = "644--658",

journal = "Nature Immunology",

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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 2024, 'Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy', Nature Immunology, vol. 25, no. 4, pp. 644-658. https://doi.org/10.1038/s41590-024-01792-2

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AU - Chen, Jonathan H.

AU - Nieman, Linda T.

AU - Spurrell, Maxwell

AU - Jorgji, Vjola

AU - Elmelech, Liad

AU - Richieri, Peter

AU - Xu, Katherine H.

AU - Madhu, Roopa

AU - Parikh, Milan

AU - Zamora, Izabella

AU - Mehta, Arnav

AU - Nabel, Christopher S.

AU - Freeman, Samuel S.

AU - Pirl, Joshua D.

AU - Lu, Chenyue

AU - Meador, Catherine B.

AU - Barth, Jaimie L.

AU - Sakhi, Mustafa

AU - Tang, Alexander L.

AU - Sarkizova, Siranush

AU - Price, Colles

AU - Fernandez, Nicolas F.

AU - Emanuel, George

AU - He, Jiang

AU - Van Raay, Katrina

AU - Reeves, Jason W.

AU - Yizhak, Keren

AU - Hofree, Matan

AU - Shih, Angela

AU - Sade-Feldman, Moshe

AU - Boland, Genevieve M.

AU - Pelka, Karin

AU - Aryee, Martin J.

AU - Mino-Kenudson, Mari

AU - Gainor, Justin F.

AU - Korsunsky, Ilya

AU - Hacohen, Nir

PY - 2024/4

Y1 - 2024/4

N2 - 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.

AB - 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.

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

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