Abstract
SummaryBackgroundAlthough 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.MethodsWe 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.FindingsWe 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.InterpretationOur findings suggest that targeting PD-L1 together with independent biological features of the stroma may enhance host antitumor immunity in NSCLC.FundingLW 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.
Highlights
The introduction of novel therapies aimed at boosting the host immune response against the tumour by blockade of the immune checkpoint molecule programmed cell death receptor 1 (PD-1) or its cognate ligand programmed cell death ligand 1 (PD-L1) has shown durable clinical responses in first and second line setting in a subset of patients with advanced non-small cell lung cancer (NSCLC) [1À5]
Single cells were stained in buffer with Fc block containing a panel of fluorescently conjugated human monoclonal antibodies directed at the following epitopes: CD45, CD14, CD31, CD235a into one channel, CD73, CD90, PD-L1, CD47 and epithelial cell adhesion molecule (EpCAM)
An IFNgdriven T-cell inflamed gene expression profile is associated with improved response to PD-1 blockade with pembrolizumab across multiple tumour types [22]
Summary
The introduction of novel therapies aimed at boosting the host immune response against the tumour by blockade of the immune checkpoint molecule programmed cell death receptor 1 (PD-1) or its cognate ligand programmed cell death ligand 1 (PD-L1) has shown durable clinical responses in first and second line setting in a subset of patients with advanced non-small cell lung cancer (NSCLC) [1À5]. This signature is linked with poor overall survival and resistance to immune checkpoint inhibitors. T cell abundance in solid tumours is associated with better outcomes, it correlates with a stroma-mediated source of immune suppression driven by TGFb1 and poor overall survival. Whether this is observed in non-small cell lung cancer (NSCLC) is unknown. 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 TGFb1. IFNg and TNFa-primed peritumoral CD90+CD73+ cells upregulate immune checkpoint molecules PD-L1 and IDO1 and secrete an array of cytokines/chemokines including TGFb1
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