High expression of cell adhesion molecule 2 unfavorably impacts survival in non-small cell lung cancer patients with brain metastases

Background: Lung cancer is one kind of malignant tumor with a high risk for morbidity and mortality compared to other solid organ malignancies. Brain metastases occur in 30-55% of non-small cell lung cancer (NSCLC) patients. Prognosis of NSCLC patients with brain metastases is very poor. Our previous study showed that cell adhesion molecule 2 (CADM2) could regulate the development of brain metastasis in NSCLC cells. Therefore, the objective of the study is to evaluate the effect of CADM2 on the prognosis of NSCLC patients with brain metastases.Methods: The expression of CADM2 was detected by quantitative real-time polymerase chain reaction (qRT-PCR) in the tissue of the primary tumor. Patients were followed up and overall survival (OS) was calculated. The relationships between CADM2 and clinicopathological features were analyzed using the chi-square test. Kaplan-Meier analysis was carried out to demonstrate the influence of CADM2 on the OS of patients. Univariate and multivariate Cox analyses were used to determine the prognosis of NSCLC patients with brain metastases.Results: A total of 139 NSCLC patients with brain metastases from the Affiliated Cancer Hospital & Institute of Guangzhou Medical University, treated between January 2015 and December 2017 were evaluated retrospectively. The expression level of CADM2 in patients ranged from 1 to 17.2677, with a median of 6.0772. Chi-square analysis showed that CADM2 gene expression level was not significantly associated with gender, age, tumor location, histological subtype, tumor T stage, extracranial metastasis, or smoking status. However, CADM2 expression was notably associated with risk for lymph node metastasis. The results of the Kaplan-Meier analysis showed that high expression [CADM2 messenger RNA (mRNA) >= 6.0772] of CADM2 was markedly associated with poor prognosis. Univariate and multivariate Cox analyses demonstrated that CADM2 was an independent risk factor for survival in NSCLC patients with brain metastases (P<0.05).Conclusions: CADM2 expression is up-regulated and closely associated with disease progression and poor prognosis in NSCLC patients with brain metastases. CADM2 expression warrants special consideration given its potential prognostic significance that might help inform clinical decision making.Pathogenesis and treatment of chronic pulmonary disease

CTLA-4 blockade drives loss of T_reg stability in glycolysis-low tumours.

Limiting metabolic competition in the tumour microenvironment may increase the effectiveness of immunotherapy. Owing to its crucial role in the glucose metabolism of activated T cells, CD28 signalling has been proposed as a metabolic biosensor of T cells &lt;sup&gt;1&lt;/sup&gt; . By contrast, the engagement of CTLA-4 has been shown to downregulate T cell glycolysis &lt;sup&gt;1&lt;/sup&gt; . Here we investigate the effect of CTLA-4 blockade on the metabolic fitness of intra-tumour T cells in relation to the glycolytic capacity of tumour cells. We found that CTLA-4 blockade promotes metabolic fitness and the infiltration of immune cells, especially in glycolysis-low tumours. Accordingly, treatment with anti-CTLA-4 antibodies improved the therapeutic outcomes of mice bearing glycolysis-defective tumours. Notably, tumour-specific CD8 &lt;sup&gt;+&lt;/sup&gt; T cell responses correlated with phenotypic and functional destabilization of tumour-infiltrating regulatory T (T &lt;sub&gt;reg&lt;/sub&gt; ) cells towards IFNγ- and TNF-producing cells in glycolysis-defective tumours. By mimicking the highly and poorly glycolytic tumour microenvironments in vitro, we show that the effect of CTLA-4 blockade on the destabilization of T &lt;sub&gt;reg&lt;/sub&gt; cells is dependent on T &lt;sub&gt;reg&lt;/sub&gt; cell glycolysis and CD28 signalling. These findings indicate that decreasing tumour competition for glucose may facilitate the therapeutic activity of CTLA-4 blockade, thus supporting its combination with inhibitors of tumour glycolysis. Moreover, these results reveal a mechanism by which anti-CTLA-4 treatment interferes with T &lt;sub&gt;reg&lt;/sub&gt; cell function in the presence of glucose