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

Abstract

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.

ICOS Gene Polymorphisms (IVS1 + 173 T/C and c. 1624 C/T) in Primary Sjögren’s Syndrome Patients: Analysis of ICOS Expression

“…It is particularly important in the physiopathology of pSS given that T cells require co-stimulatory proteins. However, the expression of the ICOS can be affected by other mechanisms such as miRNAs (such as miR-146a on Tfh cells or MiR-27a-3p in CD4+ T cells) [41,42] or RNA-binding proteins [43] that can affect the production of the protein.…”

Exosomes reveal the dual nature of radiotherapy in tumor immunology

“…As previously stated, the antigen presentation pathway is influenced, and includes costimulatory and coinhibitory factors 42,43 . Irradiation increases the expression of costimulatory molecules, resulting in immunological activation, whereas coinhibitory factors have the reverse effect.…”

“…As previously stated, the antigen presentation pathway is influenced, and includes costimulatory and coinhibitory factors. 42 , 43 Irradiation increases the expression of costimulatory molecules, resulting in immunological activation, whereas coinhibitory factors have the reverse effect. In melanoma, it has been demonstrated that the T cell immunoglobulin and ITIM domain (TIGIT), which binds to the coinhibitory factors CD155 and B7‐H3 and V‐domain containing Ig suppressor of T cell activation (VISTA), inhibits the production of IFN‐γ and TNF‐α, which initiate cell apoptosis to eliminate abnormal cells.…”

“…41 As previously stated, the antigen presentation pathway is influenced, and includes costimulatory and coinhibitory factors. 42,43 Irradiation increases the expression of costimulatory molecules, ant cancer cell in BALB/c mice injected with 4T1 cells. 47 Similarly, the inhibition of CD47 has been shown to provide significant relief for T cells that are hypersensitive to irradiation during RT in lymphomas.…”

Identification of Acute Myeloid Leukemia Bone Marrow Circulating MicroRNAs

“…Furthermore, miR-146a is also a key regulator of Treg cell biology, as deficiency of miR-146a leads to impaired function of Treg cells and consequently to the breakdown of immunological tolerance and to the development of fatal immune-mediated lesions depending on IFN-γ. Indeed, in addition to their role in the proliferation of cancer cells, many of these downregulated miRNAs, including miR-15 [ 112 , 113 ], miR-27a [ 114 , 115 ] and miR-29c [ 116 , 117 , 118 ], appear to play a role in immune regulation, T regulatory and inflammatory responses and TIL dysfunction.…”