Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer.

Wang, Limei; Yang, Haitang; Dorn, Patrick; Berezowska, Sabina; Blank, Fabian; Wotzkow, Carlos; Marti, Thomas M; Peng, Ren-Wang; Harrer, Nathalie; Sommergruber, Wolfgang; Kocher, Gregor J; Schmid, Ralph A; Hall, Sean R R (2021). Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer. EBioMedicine, 73, p. 103664. Elsevier 10.1016/j.ebiom.2021.103664

[img]
Preview
Text
1-s2.0-S2352396421004588-main.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (5MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Thoracic Surgery
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > Forschungsbereich Mu50 > Forschungsgruppe Thoraxchirurgie
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DCR Services > Core Facility Live Cell Imaging (LCI)

UniBE Contributor:

Wang, Limei; Yang, Haitang; Dorn, Patrick; Berezowska, Sabina Anna; Blank, Fabian; Wotzkow Alvarez, Carlos; Marti, Thomas; Peng, Ren-Wang; Kocher, Gregor; Schmid, Ralph and Hall, Sean

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

2352-3964

Publisher:

Elsevier

Language:

English

Submitter:

Thomas Michael Marti

Date Deposited:

18 Jan 2022 14:05

Last Modified:

23 Jan 2022 01:50

Publisher DOI:

10.1016/j.ebiom.2021.103664

PubMed ID:

34740105

Uncontrolled Keywords:

Immunosuppression Lung cancer PD-L1 Stroma T cells TGFβ1

BORIS DOI:

10.48350/162939

URI:

https://boris.unibe.ch/id/eprint/162939

Actions (login required)

Edit item Edit item
Provide Feedback