TY - JOUR
T1 - Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells
AU - Casanova-Acebes, María
AU - Dalla, Erica
AU - Leader, Andrew M.
AU - LeBerichel, Jessica
AU - Nikolic, Jovan
AU - Morales, Blanca M.
AU - Brown, Markus
AU - Chang, Christie
AU - Troncoso, Leanna
AU - Chen, Steven T.
AU - Sastre-Perona, Ana
AU - Park, Matthew D.
AU - Tabachnikova, Alexandra
AU - Dhainaut, Maxime
AU - Hamon, Pauline
AU - Maier, Barbara
AU - Sawai, Catherine M.
AU - Agulló-Pascual, Esperanza
AU - Schober, Markus
AU - Brown, Brian D.
AU - Reizis, Boris
AU - Marron, Thomas
AU - Kenigsberg, Ephraim
AU - Moussion, Christine
AU - Benaroch, Philippe
AU - Aguirre-Ghiso, Julio A.
AU - Merad, Miriam
N1 - Funding Information:
Competing interests J.A.A.-G. is a scientific co-founder of, scientific advisory board member and equity owner in HiberCell and receives financial compensation as a consultant for HiberCell, a Mount Sinai spin-off company focused on therapeutics that prevent or delay cancer recurrence. M.M. serves on the scientific advisory boards of Compugen Inc., Innate Pharma Inc., Morphic Therapeutic, Myeloid Therapeutics, Celsius Therapeutics and Genenta. M.M. receives funding from Genentech Inc., Regeneron Inc., Boerhinger Ingelheim Inc. and Takeda Inc. M.M. has ownership interest of less than 5% in Compugen Inc., Celsius Therapeutics Inc., Dren Bio Inc., and Asher Bio Inc. B.M.M., M.B. and C.M. declare that they are Genentech/Roche employees.
Funding Information:
Acknowledgements This work was supported by an HFSP postdoctoral fellowship (LT000110/2015-L/1) and an AACR–AstraZeneca Immuno-oncology Research Fellowship (20-40-12-CASA) to M.C.-A.; T32 CA078207 to A.L.; F30 CA243210 to S.T.C.; and ANR-10-IDEX-0001-02 PSL and ANR-11-LABX-0043 and Fondation ARC pour la recherche sur le cancer to P.B. This research was supported in part by the Tisch Cancer Institute at Mount Sinai P30 CA196521-Cancer Center Support Grant. We thank the Human Immune Monitoring Center for all the single-cell profiling and epigenetic studies; the Merad laboratory and A. Lujambio for discussions and reagents; the Flow Cytometry and the Imaging Core at Mount Sinai; and the Cancer Biorepository at MSSM for sample acquisition. This work was also supported by National Institutes of Health (NIH)–National Cancer Institute grants CA257195, CA254104, AT011326, AI128949 and R56AI137244 to M.M., who is also a Samuel Waxman Cancer Research Foundation Investigator; CA109182, CA216248 and CA218024 to J.A.A.-G., who is also a Samuel Waxman Cancer Research Foundation Investigator; CA257195, CA254104, AT011326 and AI128949 to B.D.B.; NCI grant T32 CA078207 to E.D.; and NIH grant AG049074 to B.R.
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2021/7/22
Y1 - 2021/7/22
N2 - Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3–5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial–mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
AB - Macrophages have a key role in shaping the tumour microenvironment (TME), tumour immunity and response to immunotherapy, which makes them an important target for cancer treatment1,2. However, modulating macrophages has proved extremely difficult, as we still lack a complete understanding of the molecular and functional diversity of the tumour macrophage compartment. Macrophages arise from two distinct lineages. Tissue-resident macrophages self-renew locally, independent of adult haematopoiesis3–5, whereas short-lived monocyte-derived macrophages arise from adult haematopoietic stem cells, and accumulate mostly in inflamed lesions1. How these macrophage lineages contribute to the TME and cancer progression remains unclear. To explore the diversity of the macrophage compartment in human non-small cell lung carcinoma (NSCLC) lesions, here we performed single-cell RNA sequencing of tumour-associated leukocytes. We identified distinct populations of macrophages that were enriched in human and mouse lung tumours. Using lineage tracing, we discovered that these macrophage populations differ in origin and have a distinct temporal and spatial distribution in the TME. Tissue-resident macrophages accumulate close to tumour cells early during tumour formation to promote epithelial–mesenchymal transition and invasiveness in tumour cells, and they also induce a potent regulatory T cell response that protects tumour cells from adaptive immunity. Depletion of tissue-resident macrophages reduced the numbers and altered the phenotype of regulatory T cells, promoted the accumulation of CD8+ T cells and reduced tumour invasiveness and growth. During tumour growth, tissue-resident macrophages became redistributed at the periphery of the TME, which becomes dominated by monocyte-derived macrophages in both mouse and human NSCLC. This study identifies the contribution of tissue-resident macrophages to early lung cancer and establishes them as a target for the prevention and treatment of early lung cancer lesions.
UR - http://www.scopus.com/inward/record.url?scp=85108157661&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-03651-8
DO - 10.1038/s41586-021-03651-8
M3 - Article
C2 - 34135508
AN - SCOPUS:85108157661
SN - 0028-0836
VL - 595
SP - 578
EP - 584
JO - Nature
JF - Nature
IS - 7868
ER -