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 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^*

^*Corresponding author for this work

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

69 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

Bibliographical note

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

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10.1038/s41590-024-01792-2

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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

@article{abf3e647a1fb4b61b9fd01cbd694ecd2,

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

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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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ER -

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

Abstract

Bibliographical note

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