大澤 英之

BACKGROUND: Recent studies reveal that during trogocytosis plasma membranes are frequently transferred upon cell-to-cell contact, and that this phenomenon plays an important role in the modulation of anti-tumor immune response. However, the accompanying physiological roles in the tumor microenvironment are poorly understood. METHODS & RESULTS: Human gastric cancer cell line OCUM-1 was co-cultured with T cells whose plasma membrane was stained with PKH26. Flow-cytometric analysis revealed that OCUM-1 was positive for PKH26 at one hour and the positive rate increased over time. The acquisition of PKH26 was dependent on cell-to-cell contact and suppressed when T cells were fixed. OCUM-1 came to express various immunological synapse molecules after 10 hours of co-culture (positive rate, CD45:73.6±7.9%, CD3: 35.5±10.1%, CD4: 15.3±14.7%, CD8: 7.7±2.4%, CD11a: 8.1±4.3%, CD11b: 3.4±1.9%). We focused on CD11a which belongs to β2 integrins and aids immune cell adherence to endothelial cells. After co-culture with activated T cells (LAK), the expression level of CD11a on OCUM-1 was accelerated (with T cells: 19.1±13.4%, with LAK: 75.2±11.8%) and the adhesion rate on endothelial cells increased in a CD11a dependent manner (adhesion rate, single-culture: 2.0±0.64%, co-culture: 6.3±2.0%, co-culture (pre-treat with CD11a antibody): 2.3±1.4%, n=10, single-culture vs co-culture, p<0.0001; co-culture vs pre-treat with CD11a antibody, p<0.0001). CONCLUSION: These results suggest that acquisition of CD11a from T cells by trogocytosis enables cancer cells to increase adhesive properties towards endothelial cells, which may result in intravenous metastasis promotion.

BACKGROUND: Neoadjuvant therapy has been increasingly adopted for resectable pancreatic ductal adenocarcinoma (PDAC) in Japan following the Prep-02/JSAP-05 trial. However, real-world evidence regarding effectiveness and underlying pathological mechanisms remains limited. This retrospective study evaluated neoadjuvant chemotherapy with gemcitabine plus S-1 (NAC-GS) impacts on resectable PDAC patient oncological and pathological outcomes. METHODS: Consecutive resectable PDAC patients treated with NAC-GS (n = 60) or upfront surgery (UFS) (n = 101) between 2013 and 2023 were retrospectively analyzed (total diagnosed during the study period, n = 186). An intention-to-treat principle assessed overall survival (OS) and recurrence-free survival (RFS). Propensity score matching using six baseline variables (1:1) minimized selection bias. RESULTS: Fifty-four patients were included in each group. The NAC-GS group demonstrated significantly longer OS than the UFS group (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.25-0.90; P = 0.023). Among resected cases, NAC-GS was associated with improved OS (HR, 0.42; 95% CI, 0.20-0.90; P = 0.026). Pathologically, the NAC-GS group showed significantly lower lymph node stage and less lymphatic invasion. Pathological complete response was observed in 4.0% of NAC-GS patients. DISCUSSION: Neoadjuvant chemotherapy with GS was associated with prolonged survival in resectable PDAC, potentially through lymphatic spread suppression. Pathological complete response was rare but may represent a clinically meaningful benefit of neoadjuvant treatment in selected patients.

BACKGROUND AND PURPOSE: The peritoneal cavity constitutes a unique immune microenvironment that critically influences the pathobiology of peritoneal metastasis (PM). This study aimed to clarify the mechanisms by which local immune alterations affect the efficacy of intraperitoneal (IP) chemotherapy for PM from gastric cancer (GC). METHOD: Peritoneal lavage or ascitic fluid was obtained from 42 patients with GC and PM treated with IP paclitaxel (PTX) in combination with systemic oxaliplatin and oral S-1. Serial samples from 31 patients were analyzed after 1-3 cycles of chemotherapy. Immune cell subsets were evaluated using multicolor flow cytometry with monoclonal antibodies, and the functional properties of peritoneal eosinophils were assessed using gene expression profiling and cytotoxicity assays. RESULTS: IP chemotherapy was associated with decreased CD4(+) T cells and increased CD11b(+) myeloid cells. Notably, many patients, particularly those with negative cytology (CY0), exhibited striking recruitment of CD66b(+) CD16(-) CD193(+) Siglec-F(+) eosinophils into the peritoneal cavity. Eosinophil expansion was correlated with improved clinical outcomes. Post-treatment eosinophils displayed an activated, partially degranulated phenotype with elevated CD11b and CD63 expression and distinct messenger RNA signatures compared with circulating eosinophils. Peritoneal eosinophils demonstrated the ability to induce apoptosis in GC cells. CONCLUSION: IP PTX promotes the recruitment and activation of eosinophils with potent antitumor activity in the peritoneal cavity. Early post-treatment abdominal eosinophilia is a robust prognostic biomarker and may represent a promising therapeutic target to enhance the efficacy of IP chemotherapy in patients with PM from GC.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is frequently associated with diabetes mellitus (DM), and their prognosis remains particularly poor. Metformin, a widely used antidiabetic agent, has demonstrated anti-tumor effects through multiple mechanisms and has been associated with improved outcomes in various malignancies. In this study, we investigated retrospectively survival outcomes and intra-tumoral infiltration patterns of various immune cells in diabetic patients who underwent curative resection of PDAC, comparing those who received metformin with those who did not. METHODS: A total of 65 diabetic patients who underwent curative resection for invasive PDAC were retrospectively analyzed. Among them, 17 patients received metformin, while 48 did not. Recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups. Following propensity score matching, tumor-infiltrating CD3(+) and CD8(+) T cells were assessed by immunohistochemistry (IHC), and their densities were compared between metformin users and non-users. RESULTS: Patients in the metformin group showed significantly prolonged RFS [hazard ratio (HR) =0.42, P=0.03] and OS (HR =0.421, P=0.03) compared to those in the non-metformin group. Multivariate analysis identified metformin use as an independent prognostic factor for both RFS (HR =0.40, P=0.02) and OS (HR =0.21, P=0.02). The survival benefit of metformin was particularly evident in patients who underwent upfront surgery, whereas not significant in those who received neoadjuvant therapy. Immunohistochemical analysis revealed a significantly higher density of CD8(+) T cells (650.7 vs. 269.9/mm2, P<0.001) with an increased CD8/CD3 ratio in resected tumors from metformin-treated patients compared to non-users (58.9% vs. 44.8%, P<0.001). This trend was kept in patients who underwent upfront surgery, while less pronounced in patients treated with neoadjuvant therapy. CONCLUSIONS: Metformin may enhance the infiltration of cytotoxic CD8(+) T cells into the tumor microenvironment and improve the prognosis of diabetic patients with PDAC, particularly in those undergoing upfront surgical resection.