Tumor-Associated Regulatory T Cell Expression of LAIR2 Is Prognostic in Lung Adenocarcinoma.

Dalam Ly,Li Zhang,Chang-Qi Zhu,Michael Cabanero,Cédric Zeltz,Roya Navab,Ming-Sound Tsao,Quan Li,Linan Fang

doi:10.3390/cancers14010205

Abstract

Simple SummaryUnderstanding how the immune system navigate the tumor microenvironment is vital to developing effective drugs to treat cancer. Using gene and functional studies, we found that the collagen receptor LAIR2 is an important component of cancer regulation. When expressed in regulatory T cells, a LAIR2 containing gene signature is adversely prognostic in lung cancer. This study highlights the importance of microenvironment regulation of immune cells and provides a unique target for future therapeutic development.Cancer development requires a permissive microenvironment that is shaped by interactions between tumor cells, stroma, and the surrounding matrix. As collagen receptors, the leukocyte-associated immunoglobulin-like receptor (LAIR) family allows the immune system to interact with the extracellular matrix. However, little is known about their role in regulating tumor immunity and cancer progression. Methods: Genetic analysis of resected human lung adenocarcinoma was correlated to clinical-pathological characteristics, gene ontologies, and single cell RNA sequencing (scRNASeq). LAIR2 production was determined in subsets of immune cells isolated from blood leukocytes and lung adenocarcinoma tumor. Functional assays were used to determine the role of LAIR2 in tumorigenesis. Results: LAIR2 expression was adversely prognostic in lung adenocarcinoma. LAIR2 was preferentially produced by activated CD4+ T cells and enhanced in vitro tumor invasion into collagen. scRNASeq analysis of tumor infiltrating T cells revealed that LAIR2 expression co-localized with FOXP3 expressing cells and shared a transcriptional signature with tumor-associated regulatory T (Treg) cells. A CD4+ LAIR2+ Treg gene signature was prognostically significant in the TCGA dataset (n = 439; hazard ratio (HR) = 1.37; 95% confidence interval (CI), 1.05–1.77, p = 0.018) and validated in NCI Director’s Challenge lung adenocarcinoma dataset (n = 488; HR = 1.54; 95% CI, 1.14–2.09, p = 0.0045). Conclusions: Our data support a role for LAIR2 in lung adenocarcinoma tumorigenesis and identify a CD4+ LAIR2+ Treg gene signature in lung adenocarcinoma prognosis. LAIR2 provides a novel target for development of immunotherapies.

Highlights

Lung cancer is the leading cause of cancer-related deaths world-wide, and 85% of patients belong to non-small cell lung cancer (NSCLC), of which lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the most common subtypes [1].Immunotherapies targeting immune checkpoint PD-1/PD-L1 interaction have become standard of care in the treatment of advanced stage NSCLC patients
High LAIR2 expression was univariately associated with poorer overall survival (OS) (Figure 1A; hazard ratio (HR) = 2.08, 95% confidence interval (CI) 1.20–3.64, p = 0.0071) in LUAD, but was not prognostic among LUSC patients (Figure 1B; HR = 1.01, 95% CI 0.39–2.61; p = 0.97)
We found that the presence of the soluble collagen receptor LAIR2 was associated with poorer prognosis in early stage LUAD patients

Summary

Introduction

Lung cancer is the leading cause of cancer-related deaths world-wide, and 85% of patients belong to non-small cell lung cancer (NSCLC), of which lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) are the most common subtypes [1].Immunotherapies targeting immune checkpoint PD-1/PD-L1 interaction have become standard of care in the treatment of advanced stage NSCLC patients. Even among patients who have high expression of PD-L1, more than 50% of patients do not respond [1,2,3] This may be partially due to our incomplete understanding of the tumor microenvironment (TME) and its relation to lung cancer biology [4,5]. Several groups have described tumor stromal immune signatures and histologically defined immune cell subsets associated with NSCLC prognosis [8,9,10]. CD4+ regulatory T (Treg) cells that express the transcription factor Foxp are an important T cell subset that are recruited to sites of inflammation and facilitate tumor progression and metastasis in most cancers [11,12,13]. A growing body of evidence indicates that tumor-associated Treg cells have unique transcriptional signatures relative to their peripheral blood counterparts [17,18,19,20,21,22]

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Results

Conclusion