Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer
Limei Wang,
Haitang Yang,
Patrick Dorn,
Sabina Berezowska,
Fabian Blank,
Carlos Wotzkow,
Thomas M. Marti,
Ren-Wang Peng,
Nathalie Harrer,
Wolfgang Sommergruber,
Gregor J. Kocher,
Ralph A. Schmid,
Sean R.R. Hall
Affiliations
Limei Wang
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland; Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland
Haitang Yang
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland; Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland
Patrick Dorn
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland
Sabina Berezowska
Institute of Pathology, University of Bern, Switzerland
Fabian Blank
Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland; DCR Live Imaging Core, University of Bern, Switzerland
Carlos Wotzkow
DCR Live Imaging Core, University of Bern, Switzerland
Thomas M. Marti
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland; Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland
Ren-Wang Peng
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland; Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland
Nathalie Harrer
Boehringer Ingelheim, RCV GmbH & Co KG, Vienna, Austria
Wolfgang Sommergruber
Boehringer Ingelheim, RCV GmbH & Co KG, Vienna, Austria
Gregor J. Kocher
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland; Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland
Ralph A. Schmid
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland; Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland; Corresponding authors at: Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland.
Sean R.R. Hall
Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland; Department of BioMedical Research, University of Bern, Murtenstrasse 50, Bern 3008, Switzerland; Corresponding authors at: Division of General Thoracic Surgery, Bern University Hospital, Bern, Switzerland.
Summary: Background: Although T cell abundance in solid tumours is associated with better outcomes, it also correlates with a stroma-mediated source of immune suppression driven by TGFβ1 and poor overall survival. Whether this also is observed in non-small cell lung cancer (NSCLC) is unknown. Methods: We utilized molecular analysis of The Cancer Genome Atlas (TCGA) NSLCC cohort to correlate immune activation (IA) gene expression and extracellular matrix/stromal (ECM/stromal) gene expression with patient survival. In an independent cohort of NSCLC samples, we used flow cytometry to identify mesenchymal subsets and ex vivo functional studies to characterize their immune regulatory function. Findings: We observed a high enrichment in a core set of genes defining an IA gene expression signature in NSCLC across TCGA Pan-cancer cohort. High IA signature score correlates with enrichment of ECM/stromal gene signature across TCGA NSCLC datasets. Importantly, a higher ratio of ECM/stromal to IA gene signature score was associated with shorter overall survival. In tumours resected from a separate cohort of NSCLC patients, we identified CD90+CD73+ peritumoral cells that were enriched in the ECM/stromal gene signature, which was amplified by TGFβ1. IFNγ and TNFα-primed peritumoral CD90+CD73+ cells upregulate immune checkpoint molecules PD-L1 and IDO1 and secrete an array of cytokines/chemokines including TGFβ1. Finally, immune primed peritumoral CD90+CD73+ cells suppress T cell function, which was relieved following combined blockade of PD-L1 and TGFβ1 with IDO1 inhibition but not PD-L1 or anti-CD73 alone. Interpretation: Our findings suggest that targeting PD-L1 together with independent biological features of the stroma may enhance host antitumor immunity in NSCLC. Funding: LW and HY are supported by a 4-year China Scholarship Council award. This work was funded, in part, by a grant from the Cancer League of Bern, Switzerland to SRRH. Laser scanning microscopy imaging was funded by the R'Equip grant from the Swiss National Science Foundation Nr. 316030_145003.
