Integrin α2 promotes immune escape in non-small-cell lung cancer by enhancing PD-L1 expression in exosomes to inhibit CD8 + T-cell activity.

This study intended to delineate the mechanism and functional role of integrin α2 (ITGA2) in non-small-cell lung cancer (NSCLC) cell immune escape. Bioinformatics analysis was utilized to analyze ITGA2 expression in NSCLC tissues, and correlations between ITGA2 expression and patient survival time, ITGA2 expression and programmed cell death ligand 1 (PD-L1; CD274) expression, and ITGA2 expression and CD8+ T-cell infiltration. Quantitative real-time polymerase chain reaction detected ITGA2 expression. Transmission electron microscopy was applied to examine the morphology of exosomes, and western blot measured CD9, CD63, and PD-L1 levels. CCK-8 measured cell viability. Cell toxicity experiment measured the killing effect of CD8+ T cells on cancer cells. Enzyme-linked immunosorbent assay assessed secretion levels of interleukin-2, interferon-gamma, tumor necrosis factor-alpha, and PD-L1 expression in exosomes. Immunohistochemistry detected ITGA2, CD8, and PD-L1 expression in patient tissue samples. ITGA2 was highly expressed in NSCLC, and Pearson correlation analysis showed a negative correlation of ITGA2 with CD8+ T-cell infiltration and a positive correlation of ITGA2 with PD-L1 expression. Cell experiments showed that silencing ITGA2 hindered NSCLC cell progression and increased levels of CD8+ T-cell secretory factors. Further mechanism studies found that ITGA2 reduced CD8+ T-cell-mediated antitumor immunity via the increase in PD-L1 expression. Clinical sample testing unveiled that ITGA2 was upregulated in NSCLC tissues. PD-L1 upregulation was seen in exosomes separated from patient blood, and correlation analysis showed a positive correlation of exosomal PD-L1 expression in blood with ITGA2 expression in tissues. This study displays a novel mechanism and role of ITGA2 in NSCLC immune escape, providing directions for the clinical therapy of NSCLC patients.

Targeting integrin α2 as potential strategy for radiochemosensitization of glioblastoma.

BACKGROUND: Glioblastoma (GBM) is a fast-growing primary brain tumor characterized by high invasiveness and resistance. This results in poor patient survival. Resistance is caused by many factors, including cell-extracellular matrix (ECM) interactions. Here, we addressed the role of adhesion protein integrin α2, which we identified in a high-throughput screen for novel potential targets in GBM cells treated with standard therapy consisting of temozolomide (TMZ) and radiation. METHODS: In our study, we used a range of primary/stem-like and established GBM cell models in vitro and in vivo. To identify regulatory mechanisms, we employed high-throughput kinome profiling, Western blotting, immunofluorescence staining, reporter, and activity assays. RESULTS: Our data showed that integrin α2 is overexpressed in GBM compared to normal brain and, that its deletion causes radiochemosensitization. Similarly, invasion and adhesion were significantly reduced in TMZ-irradiated GBM cell models. Furthermore, we found that integrin α2-knockdown impairs the proliferation of GBM cells without affecting DNA damage repair. At the mechanistic level, we found that integrin α2 affects the activity of activating transcription factor 1 (ATF1) and modulates the expression of extracellular signal-regulated kinase 1 (ERK1) regulated by extracellular signals. Finally, we demonstrated that integrin α2-deficiency inhibits tumor growth and thereby prolongs the survival of mice with orthotopically growing GBM xenografts. CONCLUSIONS: Taken together our data suggest that integrin α2 may be a promising target to overcome GBM resistance to radio- and chemotherapy. Thus, it would be worth evaluating how efficient and safe the adjuvant use of integrin α2 inhibitors is to standard radio(chemo)therapy in GBM.

The cannabinoid receptor 2 is critical for the host response to sepsis.

Leukocyte function can be modulated through the cannabinoid receptor 2 (CB2R). Using a cecal ligation and puncture (CLP) model of sepsis, we examined the role of the CB2R during the immune response to an overwhelming infection. CB2R-knock out (KO) mice showed decreased survival as compared with wild-type mice. CB2R-KO mice also had increased serum IL-6 and bacteremia. Twenty-four hours after CLP, the CB2R-deficient mice had increased lung injury. Additionally, CB2R-deficiency led to increased neutrophil recruitment, decreased neutrophil activation, and decreased p38 activity at the site of infection. Consistent with a novel role for CB2R in sepsis, CB2R-agonist treatment in wild-type mice increased the mean survival time in response to CLP. Treatment with CB2R-agonist also decreased serum IL-6 levels, bacteremia, and damage to the lungs compared with vehicle-treated mice. Finally, the CB2R agonist decreased neutrophil recruitment, while increasing neutrophil activation and p38 activity at the site of infection compared with vehicle-treated mice. These data suggest that CB2R is a critical regulator of the immune response to sepsis and may be a novel therapeutic target.