Amine oxidase, copper containing 3 exerts anti‑mesenchymal transformation and enhances CD4⁺ T‑cell recruitment to prolong survival in lung cancer

Abstract

Lung cancer remains notorious for its poor prognosis. Despite the advent of tyrosine kinase inhibitors and immune checkpoint inhibitors, the probability of curing the disease in lung cancer patients remains low. Novel mechanisms and treatment strategies are needed to provide hope to patients. Advanced strategies of next generation sequencing (NGS) and bioinformatics were used to analyze normal and lung cancer tissues from lung cancer patients. Amine oxidases have been linked to leukocyte migration and tumorigenesis. However, the roles of amine oxidases in lung cancer are not well-understood. Our results indicated that amine oxidase, copper containing 3 (AOC3) was significantly decreased in the tumor tissue compared with the normal tissue, at both the mRNA and protein level, in the included lung cancer patients and public databases. Lower expression of AOC3 conferred a poorer survival probability across the different cohorts.Epigenetic silencing of AOC3 via miR-3691-5p caused tumor promotion and progression by increasing migration and epithelial-mesenchymal transition (EMT). Furthermore, knockdown of AOC3 caused less CD4 + T-cell attachment onto lung cancer cells and reduced transendothelial migration in vitro, as well as reducing CD4 + T-cell trafficking to the lung in vivo. In conclusion, the present study revealed that downregulation of AOC3 mediated lung cancer promotion and progression, as well as decrease of immune cell recruitment. This novel finding could expand our understanding of the dysregulation of the tumor immune microenvironment and could help to develop a novel strategy for the treatment of lung cancer.

Cuproptosis depicts tumor microenvironment phenotypes and predicts precision immunotherapy and prognosis in bladder carcinoma

“…Specifically, LOX2 was found to increase ECM and prevent CD8 + T cells infiltration into TME, thus causing patients' resistance to anti-PD-L1 (32). Downregulation of amine oxidase copper containing 3 (AOC3) was reported to decrease immune cell recruitment and promote lung cancer progression (33). Importantly, as the most important copper influx transporter, copper transporter 1 (CTR-1) was found to be significantly related with PD-L1 expression and play vital role in the cancer immune evasion (19).…”

Homologous recombination repair gene‐based risk model predicts prognosis and immune microenvironment for primary lung cancer after previous malignancies

“…25 Patients with non-small cell lung cancer lacking CD4+ T cells have a worse prognosis, whereas enhancing CD4+ T cells in non-small cell lung cancer has a significant improvement in patient survival. [32][33][34] In addition, different CD4+ T cell subtypes have different roles in lung cancer. Treg cells are a class of immunomodulatory cells that play a major role in immunosuppression, and their large infiltration in the immune microenvironment of lung cancer can diminish the anticancer effect of patients, which is related to stage, treatment, and prognosis.…”

“…CD4+ T cells can also promote immune checkpoint blockade by interacting with dendritic cells 25 . Patients with non‐small cell lung cancer lacking CD4+ T cells have a worse prognosis, whereas enhancing CD4+ T cells in non‐small cell lung cancer has a significant improvement in patient survival 32–34 . In addition, different CD4+ T cell subtypes have different roles in lung cancer.…”

LINC01936 inhibits the proliferation and metastasis of lung squamous cell carcinoma probably by EMT signaling and immune infiltration

“…For instance, the upregulation of TCF21 inhibits the metastasis of esophageal squamous cell carcinoma and colorectal cancer ( Chen et al, 2018 ; Dai et al, 2016 ; Dai et al, 2017 ). AOC3 is an endothelial adhesion protein, and low-level AOC3 facilitated mesenchymal transformation and decreased CD4+ T cell recruitment to lung cancer ( Chang et al, 2021 ). The decreased AOC3 levels are correlated with lymph node and hepatic metastasis in colorectal cancer ( Toiyama et al, 2009 ).…”