Tissue-resident macrophages provide a pro-tumorigenic niche to early NSCLC cells

María Casanova-Acebes (), Erica Dalla, Andrew M. Leader, Jessica LeBerichel, Jovan Nikolic, Blanca M. Morales, Markus Brown, Christie Chang, Leanna Troncoso, Steven T. Chen, Ana Sastre-Perona, Matthew D. Park, Alexandra Tabachnikova, Maxime Dhainaut, Pauline Hamon, Barbara Maier, Catherine M. Sawai, Esperanza Agulló-Pascual, Markus Schober, Brian D. Brown, Boris Reizis, Thomas Marron, Ephraim Kenigsberg, Christine Moussion, Philippe Benaroch, Julio A. Aguirre-Ghiso and Miriam Merad ()
Additional contact information
María Casanova-Acebes: Icahn School of Medicine at Mount Sinai
Erica Dalla: Icahn School of Medicine at Mount Sinai
Andrew M. Leader: Icahn School of Medicine at Mount Sinai
Jessica LeBerichel: Icahn School of Medicine at Mount Sinai
Jovan Nikolic: Institut Curie, PSL Research University
Blanca M. Morales: Genentech
Markus Brown: Genentech
Christie Chang: Icahn School of Medicine at Mount Sinai
Leanna Troncoso: Icahn School of Medicine at Mount Sinai
Steven T. Chen: Icahn School of Medicine at Mount Sinai
Ana Sastre-Perona: New York University Grossman School of Medicine
Matthew D. Park: Icahn School of Medicine at Mount Sinai
Alexandra Tabachnikova: Icahn School of Medicine at Mount Sinai
Maxime Dhainaut: Icahn School of Medicine at Mount Sinai
Pauline Hamon: Icahn School of Medicine at Mount Sinai
Barbara Maier: Icahn School of Medicine at Mount Sinai
Catherine M. Sawai: University of Bordeaux
Esperanza Agulló-Pascual: Microscopy CoRE, Dean’s CoREs, Icahn School of Medicine at Mount Sinai
Markus Schober: New York University Grossman School of Medicine
Brian D. Brown: Icahn School of Medicine at Mount Sinai
Boris Reizis: New York University Grossman School of Medicine
Thomas Marron: Icahn School of Medicine at Mount Sinai
Ephraim Kenigsberg: Icahn School of Medicine at Mount Sinai
Christine Moussion: Genentech
Philippe Benaroch: Institut Curie, PSL Research University
Julio A. Aguirre-Ghiso: Icahn School of Medicine at Mount Sinai
Miriam Merad: Icahn School of Medicine at Mount Sinai

Nature, 2021, vol. 595, issue 7868, 578-584

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41586-021-03651-8

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