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Nat Med. 2018 Aug;24(8):1277-1289. doi: 10.1038/s41591-018-0096-5. Epub 2018 Jul 9.

Phenotype molding of stromal cells in the lung tumor microenvironment.

Author information

1
VIB Center for Cancer Biology, Leuven, Belgium. diether.lambrechts@kuleuven.vib.be.
2
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. diether.lambrechts@kuleuven.vib.be.
3
Respiratory Oncology Unit (Pneumology) and Leuven Lung Cancer Group, University Hospitals KU Leuven, Leuven, Belgium.
4
Laboratory of Pneumology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
5
VIB Center for Cancer Biology, Leuven, Belgium.
6
Laboratory for Translational Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium.
7
Laboratory for Computational Biology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
8
VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium.
9
Histopathology Expertise Center, VIB Leuven Center for Cancer Biology, VIB, Leuven, Belgium.
10
Department of Oncology, KU Leuven, Leuven, Belgium.
11
Laboratory of Genetics of Autoimmunity, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium.
12
Department of Thoracic Surgery, University Hospitals KU Leuven, Leuven, Belgium.
13
Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.
14
Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, KU Leuven, Leuven, Belgium.
15
Translational Cell & Tissue Research, Department of Imaging & Pathology, KU Leuven, Leuven, Belgium.
16
State Key Laboratory of Ophthalmology, Zhongsan Ophthalmic Center, SunYat-Sen University, Guangzhou, China.
17
VIB Center for Cancer Biology, Leuven, Belgium. bernard.thienpont@kuleuven.be.
18
Laboratory for Functional Epigenetics, Department of Human Genetics, KU Leuven, Leuven, Belgium. bernard.thienpont@kuleuven.be.

Abstract

Cancer cells are embedded in the tumor microenvironment (TME), a complex ecosystem of stromal cells. Here, we present a 52,698-cell catalog of the TME transcriptome in human lung tumors at single-cell resolution, validated in independent samples where 40,250 additional cells were sequenced. By comparing with matching non-malignant lung samples, we reveal a highly complex TME that profoundly molds stromal cells. We identify 52 stromal cell subtypes, including novel subpopulations in cell types hitherto considered to be homogeneous, as well as transcription factors underlying their heterogeneity. For instance, we discover fibroblasts expressing different collagen sets, endothelial cells downregulating immune cell homing and genes coregulated with established immune checkpoint transcripts and correlating with T-cell activity. By assessing marker genes for these cell subtypes in bulk RNA-sequencing data from 1,572 patients, we illustrate how these correlate with survival, while immunohistochemistry for selected markers validates them as separate cellular entities in an independent series of lung tumors. Hence, in providing a comprehensive catalog of stromal cells types and by characterizing their phenotype and co-optive behavior, this resource provides deeper insights into lung cancer biology that will be helpful in advancing lung cancer diagnosis and therapy.

PMID:
29988129
DOI:
10.1038/s41591-018-0096-5
[Indexed for MEDLINE]

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