Exosome miR-27a-3p secreted from adipocytes targets ICOS to promote antitumor immunity in lung adenocarcinoma.

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.

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