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. 2021 Dec 31;14(1):205.
doi: 10.3390/cancers14010205.

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

Dalam Ly  1   2 , Quan Li  3 , Roya Navab  3 , Cédric Zeltz  3 , Linan Fang  1 , Michael Cabanero  3 , Chang-Qi Zhu  3 , Ming-Sound Tsao  3   4 , Li Zhang  1   2   4
Affiliations

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

Dalam Ly et al. Cancers (Basel). .

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.

Keywords: LAIR2; Treg cells; collagen receptor; human lung carcinoma; prognostic gene.

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Conflict of interest statement

The authors have no potential conflicts of interest to disclose.

Figures

Figure 1
Figure 1
LAIR2 expression is associated with negative prognosis in LUAD. (A), Univariate Kaplan–Meier plots showing OS of LUAD patients or (B), LUSC patients within the UHN181.
Figure 2
Figure 2
LAIR2 expression is associated with immune cells and secreted by CD4+ T cells. (A), Left, ontological networks formed using ClueGO/CluePedia from genes co-expressed with LAIR2 (Table S2). Right, bar graph shows number of genes and significance of GO. Square brackets denote GO level hierarchy with terms on the lower levels (greater number) being more specific, while terms on higher levels being more general in their biological definition. (B), LAIR2 secretion by sorted PBMCs stimulated with PMA/ionomycin for 4 d or left unstimulated, data are representative of two healthy donors. *** p < 0.0001 as indicated, determined by two-way ANOVA test.
Figure 3
Figure 3
LAIR2 expression enhances NSCLC tumor invasion into collagen matrix. (A,B), HCC4006 and HCC827 NSCLC adherence was measured towards indicated immobilized proteins, or in the presence of soluble rhLAIR2. Non-adherent cells were removed after 40 min and adherent cells were quantified using crystal violet absorption and measured by spectrophotometry. Images taken at 4× magnification. Red scale bars = 500 µm (C,D), HCC4006 and HCC827 tumor invasion into collagen was measured in the presence of paracrine LAIR2. HCC4006 and HCC827 spheroids were embedded in type 1 collagen containing T cell line Hut78 transduced to express LAIR2 or mock (GFP) vector. Migration area from initial spheroid (in blue) was determined after 8 d of co-culture using texture analysis. Black scale bars = 200 µm. Data are representative of two independent experiments. p-values were determined by Mann–Whitney test.
Figure 4
Figure 4
LAIR2 is a marker of tumor-associated Foxp3+ Treg cells. (A), t-SNE plots of LAIR2 and T cell co-receptors from scRNASeq dataset of NSCLC patient tumors. (B), scRNASeq dataset displayed as histogram of LAIR2 expression and as pseudocolor density plots of individual cells with frequency and number of events for indicated genes within quadrants and gates. (C), LAIR2 secretion by expanded TILs stimulated with PMA/ionomycin for 4 d. Dots represent individual patient TILs expansions. p-value was determined using one-way ANOVA with Turkey’s post-test. (D), t-SNE plot of Foxp3 and volcano plot of genes expressed by CD4+ T cells with high or low expression of LAIR2 at cut-off of ≥4 log2 (TPM + 1) expression. Displayed are t-SNE dimensions 1 and 2, with each data point representing a single cell, colored by the intensity of expression log2 (TPM + 1) of indicated gene. scRNASeq displayed as pseudocolor density plot of individual cells with frequency of events for indicated gates.
Figure 5
Figure 5
Tumor-associated CD4+ LAIR2+ gene signature is prognostic in NSCLC validation. Kaplan–Meier plots showing OS of LUAD patients in (A), TCGA, (B), NCI Director’s Challenge Consortium datasets, patients were divided into two risk groups based on the median value of the gene signature risk scores. Number at risk indicates the number of participants who are event free at indicated times. (C), Schematic of LAIR2 activity. LAIR2 is a secreted protein that interacts with collagen through its Ig domain. In contrast to LAIR1, LAIR2 lacks transmembrane and signaling domains. Amongst tumor infiltrating T cells, LAIR2 was found to be predominately expressed by tumor-associated Foxp3+ Treg cells by scRNASeq. As a ligand for collagen, autocrine LAIR2 may help Treg cells function in a collagen dense environment. In addition, LAIR2 was found to act in a paracrine fashion by increasing tumor migration and invasion into collagen matrix. As a mechanism, LAIR2 inhibits tumor cell adhesion on collagen that could initiate tumor migration and invasion. Along with inhibition of adhesion, interaction of LAIR2 with a cell receptor that mediates signaling leading to cell invasion cannot be excluded.
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