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

Abstract

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.

Screening of Key Prognosis Genes of Lung Adenocarcinoma Based on Expression Analysis on TCGA Database

“…According to the latest report of the Global Cancer Statistics Center, lung cancer has the highest incidence and mortality among all male patients with malignant tumors, while the incidence of lung cancer in female patients is lower than that of breast cancer and colon cancer, and the mortality rate is second only to that of breast cancer [ 1 ]. Lung adenocarcinoma (LUAD) is the most common pathological type of non-small-cell lung cancer, accounting for 85% of the incidence of lung cancer [ 2 , 3 ]. In recent years, it has been characterized by rapid onset, younger age, high mortality, and poor prognosis.…”

Unraveling the tumor immune microenvironment of lung adenocarcinoma using single-cell RNA sequencing

“…The prognostic markers and the indications for prognosis in these studies are summarized in Table 2 . 36 , 44 , 45 , 47 – 49 , 55 – 89 DEGs and their combined prognostic model were the most common types of prognostic markers in these studies. For example, one study identified nine cancer-specific DEGs (CBFA2T3, CR2, SEL1L3, TM6SF1, TSPAN32, ITGA6, MAPK11, RASA3, and TLR6) and established a prognostic risk model in combination with clinical factors.…”

“…A CD4+ LAIR2+ Treg gene signature was prognostically significant in the The Cancer Genome Atlas (TCGA) dataset. 67 Another study reported that patients with low gene transcription of CXC ligand (CXCL) 7 and high expression of CXCL 17 had a better prognosis in LUAD. Immune cell infiltration, specifically B-cell infiltration was significantly correlated with LUAD microenvironment mediated by cysteine(C)-non cysteine(X)-cysteine(C) (CXC) chemokines.…”

Extracellular matrix remodeling in the tumor immunity

“…The noteworthy role of LAIR2 lies in its ability to augment the adherence of tumor cells to collagen I, a substantial constituent of the ECM. This mechanism assumes particular significance in the context of lung adenocarcinoma, wherein elevated LAIR2 expression in tumor-associated Treg cells correlates with heightened tumor advancement and metastasis ( 95 ).…”