Could Toll-like Receptor 2 Serve as Biomarker to Detect Advanced Gastric Cancer?

{"Background": "Gastric cancer remains one of the five most common cancers worldwide, with epidemiological data predicting an increase from 1.09 million new cases in 2020 to 1.77 million by 2040, and deaths rising from 769,000 to 1.27 million. Toll-like receptors (TLRs), particularly TLR2, have been implicated in gastric cancer pathogenesis through their roles in innate and adaptive immunity. TLR2 can participate in both anti-cancer and pro-carcinogenic mechanisms, including maintaining intestinal integrity, promoting inflammation, increasing proliferation and survival of gastric epithelial cells, and metabolic reprogramming. This study aimed to determine the prevalence of TLR2 on T lymphocytes, B lymphocytes, monocytes, and dendritic cells in gastric cancer patients, with emphasis on disease stage.", "Methods": "The study included 40 treatment-na\u00efve gastric cancer patients (24 men, 16 women; mean age 62.7 \u00b1 10.5) and 25 age-matched healthy controls (15 men, 10 women; mean age 62.3 \u00b1 9.5). Exclusion criteria included immunosuppressive medications, hormonal therapy, infection within three months, blood transfusion history, autoimmune disease, cancer, allergies, and pregnancy/lactation. Peripheral blood samples (10 mL) were collected one day before surgery. Flow cytometry was used to assess TLR2 expression on T helper cells (CD3+CD4+), cytotoxic T cells (CD3+CD8+), B lymphocytes (CD3\u2212CD19+), NK cells (CD3\u2212CD16+CD56+), NKT-like cells (CD3+CD16+CD56+), myeloid dendritic cells (BDCA1+CD19-), plasmacytoid dendritic cells (BDCA2+CD123+), classical monocytes (CD14+CD16-), and non-classical monocytes (CD14+CD16+). Soluble TLR2 (sTLR2) concentration was measured using the RayBio Human TLR2 ELISA Kit (sensitivity 0.32 ng/mL). Statistical analysis used Tibco Statistica 13.3 with Shapiro-Wilk normality testing, t-test, Mann-Whitney U test, Kruskal-Wallis test, and ROC curve analysis.", "Key Results": "Gastric cancer patients showed a statistically significant decrease in peripheral blood lymphocytes compared to controls. The percentage of NK cells CD3-CD16+CD56+ and classical monocytes CD14+CD16- was significantly decreased in gastric cancer patients, while plasmacytoid dendritic cells BDCA2+CD123+ and non-classical monocytes CD14+CD16+ were increased. All tested immune cell populations expressing TLR2 were statistically significantly higher in gastric cancer patients versus controls. Serum sTLR2 concentration showed a four-fold increase in gastric cancer patients compared to healthy controls. By Lauren classification, the diffuse type (D) showed increased TLR2+ cells compared to intestinal type (I): 2.08-fold for CD4+ T cells, 2.57-fold for CD8+ T cells, 1.79-fold for CD19+ B cells, 2.48-fold for myeloid dendritic cells, and 2.0-fold for plasmacytoid dendritic cells. Diffuse type patients also had a 1.68-fold increase in sTLR2 concentration. With increasing grade (G1\u2013G3), there was a statistically significant increase in TLR2 expression on almost all tested immune cell populations except classical monocytes CD14+CD16-, along with increasing sTLR2 concentration. Similarly, with advancing TNM stage (Stage I\u2013IV), there was a statistically significant increase in TLR2 expression on almost all tested populations except plasmacytoid dendritic cells BDCA2+CD123+, and a significant increase in sTLR2 concentration. ROC curve analysis confirmed diagnostic accuracy of TLR2 expression on CD4+ T lymphocytes and non-classical monocytes CD14+CD16+, as well as sTLR2 concentration measurement.", "Clinical Implications": "The findings demonstrate that TLR2 expression on peripheral blood immune cells increases with gastric cancer progression, suggesting its potential utility as a diagnostic and staging biomarker. The ROC analysis supports the diagnostic usefulness of assessing TLR2 on CD4+ T lymphocytes and non-classical monocytes, as well as measuring sTLR2 serum concentration. These results align with prior research showing TLR2 involvement in promoting cancer cell growth through upregulation of anti-apoptotic genes (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and downregulation of tumor suppressor genes (PDCD4, TP53INP1). The study adds to evidence that TLR2 signaling may directly regulate CD8+ T lymphocyte function and facilitate gastric cancer pathogenesis and progression. However, the authors acknowledge that the specific mechanisms of TLR2 involvement in gastric cancer are not yet fully understood, and further interdisciplinary studies are needed to determine the role of TLR agonists as potential therapeutic agents."}