Single-cell and spatial transcriptomics analysis of non-small cell lung cancer.

Lung cancer is the second most frequently diagnosed cancer and the leading cause of cancer-related mortality worldwide. Tumour ecosystems feature diverse immune cell types. Myeloid cells, in particular, are prevalent and have a well-established role in promoting the disease. In our study, we profile approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma by single-cell and spatial transcriptomics. We note an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, and with reduced NK cell cytotoxicity within the tumour. While we observe a similar cell type composition in both adenocarcinoma and squamous-cell carcinoma, we detect significant differences in the co-expression of various immune checkpoint inhibitors. Moreover, we reveal evidence of a transcriptional "reprogramming" of macrophages in tumours, shifting them towards cholesterol export and adopting a foetal-like transcriptional signature which promotes iron efflux. Our multi-omic resource offers a high-resolution molecular map of tumour-associated macrophages, enhancing our understanding of their role within the tumour microenvironment.

Description

Acknowledgements: The authors are greatly thankful to the Papworth Hospital Research Tissue Bank for providing samples with data, and in particular to D. Rassl. The authors would like to thank L. Campos for the annotation of tumour histologies; A.M. Ranzoni, B. Myers and E. Panada for sample collection and processing; M. Nelson for computational support with initial clustering of scRNA-Seq and application of cell2location; Alessandro Di Tullio, GSK for insightful discussions; Cancer Research UK Cambridge Institute (CRUK CI) (Grant # CTRQQR-2021\100012) Genomics Core Facility for library preparation and sequencing services; Wellcome Sanger Institute (WSI) DNA pipelines for their contribution to sequencing the data; S. Leonard from New Pipeline Group (NPG) for pre-processing of sequencing data; the Cambridge NIHR BRC Cell Phenotyping Hub for support with cell sorting. We thank R. Möller, P. Rainer, and U. Tiemann for critically reading the manuscript. This study was conceived and funded by Open Targets (OTAR2060, A.C.); Core support grants from the Wellcome Trust and Wellcome Sanger Institute and both Wellcome and the MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z, A.C.); European Research Council (CONTEXT 101043559, A.C.); Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Research Council Executive Agency. Neither the European Union nor the granting authority can be held responsible for them.

Funder: Open Targets (OTAR2060); Core support grants from the Wellcome Trust and Wellcome Sanger Institute and both Wellcome and the MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute (203151/Z/16/Z); European Research Council (CONTEXT 101043559); Cancer Research UK Cambridge Institute (CRUK CI) (Grant # CTRQQR-2021\100012).

Keywords

Humans, Carcinoma, Non-Small-Cell Lung, Lung Neoplasms, Single-Cell Analysis, Tumor Microenvironment, Transcriptome, Gene Expression Regulation, Neoplastic, Killer Cells, Natural, Gene Expression Profiling, Macrophages, Carcinoma, Squamous Cell, Adenocarcinoma, Tumor-Associated Macrophages

Journal Title

Nat Commun

Journal ISSN

2041-1723
2041-1723

Volume Title

15

Publisher

Springer Science and Business Media LLC

Publisher DOI

https://doi.org/10.1038/s41467-024-48700-8

Rights

Attribution 4.0 International

Sponsorship

EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council) (CONTEXT 101043559)
Cancer Research UK (CRUK) (CTRQQR-2021\100012)

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