Background: The clinical benefit of immunotherapy has been limited to a small subset of patients with cancer. Several clinical trials with immune checkpoint inhibitors in multiple cancers have shown some improvement in obese patients. However, how obesity regulates the immune microenvironment remains unclear. Methods: Bioinformatic analysis was used to discover immune microenvironmental-related genes associated with body mass index (BMI). The expression of ICOS in tumor tissues was detected using western blot, immunohistochemistry, quantitative real-time polymerase chain reaction (RT-qPCR) and flow cytometry. RT-qPCR was used to measure the expression of miR-27a-3p. The interaction between miR-27a-3p and ICOS was confirmed by dual-luciferase reporter assay. Functional testing of T cells based on proliferation and interferon (IFN)-gamma secretion was performed using ELISA and flow cytometry. Results: ICOS, an immune microenvironment-related gene, was significantly upregulated in obese patients with lung adenocarcinoma (LUAD). MiR-27a-3p showed a negative correlation with ICOS and suppressed the expression of ICOS. We determined that dipocyte-derived exo-miR-27a-3p could alter the tumor microenvironment by inhibiting ICOS + T cell proliferation and IFN-gamma secretion in vitro. Conclusions: Adipocyte-derived exo-miR-27a-3p can inhibit ICOS + T cell proliferation and IFN-gamma secretion. The upregulation of ICOS + T cell functions caused by the downregulation of miR-27a-3p in adipose tissue derived exosomes is one of the potential mechanisms for the improved efficacy of immunotherapy in obese LUAD patients.
BackgroundMitochondria are the core organelle of cellular energy and metabolism, also closely related to the growth and survival of cancer cells. This research aimed to discover and evaluate a promising prognostic biomarker, a novel mitochondrial gene—Sideroflexin1 (SFXN1), for lung adenocarcinoma (LUAD).ResultsAnalysis of 594 samples from The Cancer Genome Atlas (TCGA) Lung Cancer Cohort, this present study indicated that SFXN1/2/4/5 were overexpressed in LUAD tissue compared with normal lung tissue whereas only the SFXN1 was associated significantly with the overall survival (OS) from the Kaplan-Meier survival analysis (p=0.00093), suggesting that SFXN1 could be a potential prognostic biomarker. Furthermore, the logistic regression of the correlation of clinicopathological features and the expression status of SFXN1 from 522 patients with LUAD in TCGA revealed that the expression level of SFXN1 was related to Eastern Cooperative Oncology Group (ECOG), clinical stage, tumor size and lymph nodes invasion (all p<0.05). Additionally, overexpression of SFXN1 remained associated positively and independently with a worse prognosis after the multivariate Cox regression (HR=1.486, p=0.022). Functionally, SFXN1 involved in the cell cycle, specifically in DNA replication and meiosis, ATPase activity and folate-dependent one-carbon metabolism from the outcomes of Eastern Cooperative Oncology Group (KEGG) and Gene Ontology (GO) enrichment. ConclusionSFXN1 might promote the proliferation and metabolism of cancer cells and function as a prognostic indicator for LUAD, which may contribute to the development of targeted therapy and the emergence of metabolism-based treatment in clinical practice.
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