The interaction between cancer cells and immune cells plays critical roles in gastric cancer (GC) progression and immune evasion. Forced legumain (LGMN) is one of the characteristics correlated with poor prognosis in gastric cancer patients. However, the role of gastric-cancer-secreted LGMN (sLGMN) in modulating the tumor immune microenvironment and the biological effect on the immune evasion of gastric cancer remains unclear. In this study, we found that forced expression of sLGMN in gastric cancer serum correlates with increased M2 macrophage infiltration in GC tissues and predicted resistance to anti-PD-1 immunotherapy. Mechanistically, gastric cancer cells secrete LGMN via binding to cell surface Integrin αvβ3, then activate Integrin αvβ3/PI3K (Phosphatidylinositol-4,5-bisphosphate3-kinase)/AKT (serine/threonine kinase)/mTORC2 (mammalian target of rapamycin complex 2) signaling, promote metabolic reprogramming, and polarize macrophages from the M1 to the M2 phenotype. Either blocking LGMN, Integrin αv, or knocking out Integrin αv expression and abolishing the LGMN/Integrin αvβ3 interaction significantly inhibits metabolic reprogramming and polarizes macrophages from the M1 to the M2 phenotype. This study reveals a critical molecular crosstalk between gastric cancer cells and macrophages through the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis in promoting gastric cancer immune evasion and resistance to anti-PD-1 immunotherapy, indicating that the sLGMN/Integrinαvβ3/PI3K/AKT/mTORC2 axis may act as a promising therapeutic target.

Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors (TKIs), possess immunomodulatory properties and have shown promising outcomes when combined with anti-PD-1 antibodies. The OASIS phase II trial (NCT04503967) is designed to determine the clinical activity and safety of nivolumab (anti-PD-1) and anlotinib hydrochloride (a multi-targets TKI) as second-line or above therapy in patients with advanced gastric adenocarcinoma (GAC) and esophageal squamous cell carcinoma (ESCC). From December 2020 to September 2022, 45 patients with GAC and 3 with ESCC were enrolled in this study. The pre-specified endpoints were reached, with the primary endpoint of overall response rate achieving 29.2%. For secondary objectives, disease control rate was 64.6%; median progression-free survival was 4.0 months; and median overall survival was 11.1 months with a manageable toxicity profile. The exploratory analyses unveiled that the balance of gut bacteria and the presence of a pre-existing immune signature characterized by a high percentage of CD68⁺PD-L1⁺ PD-1⁺ macrophages and low pretreatment variant allele frequencies (VAF), as well as low expression of certain cytokines were significantly associated with improved clinical outcomes in patients with GAC.

The aim of this study was to compare the efficacies of the XELOX and DOS regimens as preoperative chemotherapy in patients with locally advanced gastric cancer. All cases of locally advanced gastric cancer treated with the XELOX or DOS regimen were reviewed retrospectively. Propensity score matching (PSM) was carried out to reduce selection bias based on age, gender, location, Lauren type, carcinoembryonic antigen level, clinical tumor stage, and clinical node stage. From January 2010 to December 2016, 248 patients were matched; 159 of them received the XELOX regimen and 89 the DOS regimen. The response rates in the XELOX and DOS groups were 34.5 and 38.1%, respectively (P = 0.823). After four cycles of chemotherapy, 111 patients (69.8%) in the XELOX group and 65 patients (73.0%) in the DOS group underwent radical surgery (P = 0.485). The median progression-free survival (33.0 months vs. 18.7 months, P = 0.0356) and the median overall survival (43.8 months vs. 29.1 months, P = 0.0003) were longer for patients who received the DOS regimen than for those who received the XELOX regimen. The occurrence of grade 3 to 4 toxicity was similar in the two groups. For locally advanced gastric cancer patients, the DOS regimen showed more benefit than the XELOX regimen as preoperative chemotherapy, without any added toxicity effects.