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

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. Metho...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	Stroma PD-L1 T cells Immunosuppression TGFβ1 Lung cancer Medicine R Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/1f7d51f1822442cc8888fbc4d5daa6bb
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spelling	oai:doaj.org-article:1f7d51f1822442cc8888fbc4d5daa6bb2021-11-04T04:32:38ZPeritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer2352-396410.1016/j.ebiom.2021.103664https://doaj.org/article/1f7d51f1822442cc8888fbc4d5daa6bb2021-11-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352396421004588https://doaj.org/toc/2352-3964Summary: 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.Limei WangHaitang YangPatrick DornSabina BerezowskaFabian BlankCarlos WotzkowThomas M. MartiRen-Wang PengNathalie HarrerWolfgang SommergruberGregor J. KocherRalph A. SchmidSean R.R. HallElsevierarticleStromaPD-L1T cellsImmunosuppressionTGFβ1Lung cancerMedicineRMedicine (General)R5-920ENEBioMedicine, Vol 73, Iss , Pp 103664- (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Stroma PD-L1 T cells Immunosuppression TGFβ1 Lung cancer Medicine R Medicine (General) R5-920
spellingShingle	Stroma PD-L1 T cells Immunosuppression TGFβ1 Lung cancer Medicine R Medicine (General) R5-920 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 Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer
description	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.
format	article
author	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
author_facet	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
author_sort	Limei Wang
title	Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer
title_short	Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer
title_full	Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer
title_fullStr	Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer
title_full_unstemmed	Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer
title_sort	peritumoral cd90+cd73+ cells possess immunosuppressive features in human non-small cell lung cancer
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/1f7d51f1822442cc8888fbc4d5daa6bb
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Peritumoral CD90+CD73+ cells possess immunosuppressive features in human non-small cell lung cancer

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