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

Nat Immunol. 2024 Apr;25(4):644-658. doi: 10.1038/s41590-024-01792-2. Epub 2024 Mar 19.

Authors

Jonathan H Chen^#^{1

2

3

4}, Linda T Nieman^#^{5

6}, Maxwell Spurrell^#^{5

7

8}, Vjola Jorgji^{5

7

8}, Liad Elmelech^{5

7

8}, Peter Richieri⁵, Katherine H Xu⁵, Roopa Madhu^{6

9}, Milan Parikh^{5

8}, Izabella Zamora⁸, Arnav Mehta^{5

8

6}, Christopher S Nabel^{5

6

10}, Samuel S Freeman^{8

6}, Joshua D Pirl^{8

11}, Chenyue Lu⁵, Catherine B Meador^{6

12}, Jaimie L Barth⁷, Mustafa Sakhi¹³, Alexander L Tang⁸, Siranush Sarkizova⁸, Colles Price¹⁴, Nicolas F Fernandez¹⁴, George Emanuel¹⁴, Jiang He¹⁴, Katrina Van Raay¹⁵, Jason W Reeves¹⁵, Keren Yizhak¹⁶, Matan Hofree^{8

17

18}, Angela Shih^{7

6}, Moshe Sade-Feldman^{5

8

6

19}, Genevieve M Boland^{8

6

20}, Karin Pelka^{5

8

21}, Martin J Aryee^{8

6

22}, Mari Mino-Kenudson^{5

7

6}, Justin F Gainor^#^{23

24

25}, Ilya Korsunsky^#^{26

27

28}, Nir Hacohen^#^{29

30

31}

Affiliations

¹ Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA. jhchen@broadinstitute.org.
² Department of Pathology, MGH, Boston, MA, USA. jhchen@broadinstitute.org.
³ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. jhchen@broadinstitute.org.
⁴ Harvard Medical School, Boston, MA, USA. jhchen@broadinstitute.org.
⁵ Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA.
⁶ Harvard Medical School, Boston, MA, USA.
⁷ Department of Pathology, MGH, Boston, MA, USA.
⁸ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA.
⁹ Brigham and Women's Hospital, Division of Genetics, Boston, MA, USA.
¹⁰ Koch Institute for Integrative Cancer Research, Department of Biology, MIT, Cambridge, MA, USA.
¹¹ Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
¹² Department of Medicine, Division of Hematology/Oncology, MGH, HMS, Boston, MA, USA.
¹³ Center for Thoracic Cancers, MGH, Boston, MA, USA.
¹⁴ Vizgen, Cambridge, MA, USA.
¹⁵ NanoString Technologies, Seattle, WA, USA.
¹⁶ Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel.
¹⁷ School of Computer Science and Engineering, The Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁸ Lautenberg Center for Immunology and Cancer Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
¹⁹ Department of Medicine, Harvard Medical School, Boston, MA, USA.
²⁰ Department of Surgery, MGH, Boston, MA, USA.
²¹ Gladstone-UCSF Institute of Genomic Immunology, Gladstone Institutes, San Francisco, CA, USA.
²² Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, USA.
²³ Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA. jgainor@mgh.harvard.edu.
²⁴ Harvard Medical School, Boston, MA, USA. jgainor@mgh.harvard.edu.
²⁵ Center for Thoracic Cancers, MGH, Boston, MA, USA. jgainor@mgh.harvard.edu.
²⁶ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. ikorsunsky@bwh.harvard.edu.
²⁷ Harvard Medical School, Boston, MA, USA. ikorsunsky@bwh.harvard.edu.
²⁸ Brigham and Women's Hospital, Division of Genetics, Boston, MA, USA. ikorsunsky@bwh.harvard.edu.
²⁹ Massachusetts General Hospital (MGH) Cancer Center, Harvard Medical School (HMS), Boston, MA, USA. nhacohen@mgh.harvard.edu.
³⁰ Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, USA. nhacohen@mgh.harvard.edu.
³¹ Harvard Medical School, Boston, MA, USA. nhacohen@mgh.harvard.edu.

^# Contributed equally.

PMID: 38503922
DOI: 10.1038/s41590-024-01792-2

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.

MeSH terms

CD8-Positive T-Lymphocytes
Chemokines / metabolism
Humans
Immunotherapy / methods
Lung Neoplasms*
Programmed Cell Death 1 Receptor
Tumor Microenvironment

Substances

Programmed Cell Death 1 Receptor
Chemokines