Peritumoral CD90 +CD73 + Cells Possess Immunosuppressive Features in Human Non-Small Cell Lung Cancer
| العنوان: | Peritumoral CD90 +CD73 + Cells Possess Immunosuppressive Features in Human Non-Small Cell Lung Cancer |
|---|---|
| المؤلفون: | Nathalie Harrer, Patrick Dorn, Thomas M. Marti, Limei Wang, Sabina Berezowska, Ralph A. Schmid, Carlos Wotzkow, Fabian Blank, Haitang Yang, Wolfgang Sommergruber, Ren-Wang Peng, Sean Hall |
| المصدر: | SSRN Electronic Journal. |
| بيانات النشر: | Elsevier BV, 2019. |
| سنة النشر: | 2019 |
| مصطلحات موضوعية: | Stromal cell, biology, business.industry, T cell, Mesenchymal stem cell, Cancer, Gene signature, medicine.disease, Immune system, medicine.anatomical_structure, PD-L1, medicine, Cancer research, biology.protein, Lung cancer, business |
| الوصف: | Background: Although T cell abundance in solid tumors is associated with better outcomes, it also correlates with a stromamediated 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, higher ratio of ECM/stromal to IA gene signature score was associated with shorter overall survival. In tumors 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, TGFβ1 and IDO1 but not PD-L1 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 Statement: 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. Declaration of Interests: The authors declare no potential conflicts of interest. Ethics Approval Statement: The study was approved by Ethics Commission of the Canton of Bern (KEK BE:042/2015). All patients gave informed written consent for use of surgical material for research purposes. |
| تدمد: | 1556-5068 |
| DOI: | 10.2139/ssrn.3474495 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::fb44825b1dddeb36dbd210ca1f3c141b https://doi.org/10.2139/ssrn.3474495 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi...........fb44825b1dddeb36dbd210ca1f3c141b |
| قاعدة البيانات: | OpenAIRE |
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