Epithelial-mesenchymal transition (EMT) signature is inversely associated with T-cell infiltration in non-small cell lung cancer (NSCLC)

Young Kwang Chae,Sangmin Chang,Wooyoung M Choi,Taeyeong Ko,Jonathan Anker,Marcelo Cruz,Wade Iams,Kyoungmin Lee,Sarita Agte

doi:10.1038/s41598-018-21061-1

Abstract

Epithelial-mesenchymal transition (EMT) is able to drive metastasis during progression of multiple cancer types, including non-small cell lung cancer (NSCLC). As resistance to immunotherapy has been associated with EMT and immune exclusion in melanoma, it is important to understand alterations to T-cell infiltration and the tumor microenvironment during EMT in lung adenocarcinoma and squamous cell carcinoma. We conducted an integrated analysis of the immune landscape in NSCLCs through EMT scores derived from a previously established 16 gene signature of canonical EMT markers. EMT was associated with exclusion of immune cells critical in the immune response to cancer, with significantly lower infiltration of CD4 T-cells in lung adenocarcinoma and CD4/CD8 T-cells in squamous cell carcinoma. EMT was also associated with increased expression of multiple immunosuppressive cytokines, including IL-10 and TGF-β. Furthermore, overexpression of targetable immune checkpoints, such as CTLA-4 and TIM-3 were associated with EMT in both NSCLCs. An association may exist between immune exclusion and EMT in NSCLC. Further investigation is merited as its mechanism is not completely understood and a better understanding of this association could lead to the development of biomarkers that could accurately predict response to immunotherapy.

Highlights

A plethora of studies have shown that the innate and adaptive immune systems play a crucial role in the anticancer response as they recognize and destroy cancer cells by a process known as cancer immunosurveillance[1,2]
T-cell suppression, we sought to determine which immune cells were excluded from the tumor microenvironment (TME) in non-small cell lung cancer (NSCLC)
In comparing the fold change of infiltration of immune cells based on Epithelial-mesenchymal transition (EMT) status, we observed an increased infiltration of cells with anti-tumor or immune stimulatory functions such as Th17, mature dendritic cells, and activated CD4 T-cells in ‘epithelial’ lung ADC

Summary

Introduction

A plethora of studies have shown that the innate and adaptive immune systems play a crucial role in the anticancer response as they recognize and destroy cancer cells by a process known as cancer immunosurveillance[1,2]. The major constituents of this defense system are tumor antigen-specific cytotoxic T-lymphocytes (CTLs), whose anti-tumor functions are amplified by immune checkpoint blockade antibodies such as CTLA-4 inhibitors and PD-1/PD-L1 inhibitors[3,4,5,6] Though such treatment modalities have shown success in select cancer types including melanoma and non-small cell lung cancer (NSCLC), the majority of cancer types are unresponsive to these treatments. Only a subset of patients can be treated due to the low baseline level of CD8 T-cell infiltration within the tumor microenvironment (TME) necessary to achieve therapeutic benefit[5,7,8] The lack of such effector cells in the TME is known as immune exclusion[9], which has been known to be mediated by the β-catenin pathway in melanoma, leading to resistance to immunotherapy[7,10,11,12]. Given that infiltration of T-cells in the TME impacts response to immune checkpoint inhibitors, understanding the association between immune exclusion, especially that of CD8 T-cells, and EMT would be of value in the development of biomarkers capable of accurately predicting response to immunotherapeutic modalities

Methods

Results

Conclusion