Myeloid-derived suppressor cells correlate with patient outcomes in hepatic arterial infusion chemotherapy for hepatocellular carcinoma

Hepatic arterial infusion chemotherapy (HAIC) has been employed as an alternative therapy to sorafenib for the patients with advanced hepatocellular carcinoma (HCC). In this study, we performed a comparative analysis of various immune cell responses including tumor-associated antigen (TAA)-specific T cells, regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) in advanced HCC patients treated with HAIC. Thirty-six HCC patients were examined in the study. Interferon gamma enzyme-linked immunospot assays were performed to examine the frequency of TAA-specific T cells. The frequencies of Tregs and MDSCs were examined by multicolor fluorescence-activated cell sorting analysis. The treatment with HAIC using interferon (IFN)/5-fluorouracil (FU) or IFN/FU + cisplatin modulated the frequencies of various immune cells. In 22.2 % of patients, the frequency of TAA-specific T cells increased after HAIC. Although the frequency of Tregs decreased after HAIC, it was not associated with the prognosis of patients. An analysis of prognostic factors for overall survival identified diameter of the tumor (<3.0 cm), absence of major portal vein invasion, absence of distant metastasis, Union Internationale Contre Le Cancer tumor lymph node metastasis stage (I or II), neutrophil lymphocytic ratio (<2.1) and the frequency of MDSCs (<30.5 %) as factors that prolonged overall survival time after HAIC. Even in the group adjusted with progressive levels of tumors, patients with a low frequency of MDSCs had a significantly longer overall survival time. In conclusion, the frequency of MDSCs before the treatment is a prognostic factor in HAIC against HCC. © 2016 Springer-Verlag Berlin Heidelber

日本における統計学の発展 第１５巻

昭和55，56，57年度文部省科学研究費総合（A）研究代表者西平重喜による速記録話し手：北原, 一身聞き手：清水, 一郎1981-1-14 | 1981-1-2

Phase I trial of multidrug resistance-associated protein 3-derived peptide in patients with hepatocellular carcinoma

Multidrug resistance-associated protein 3 (MRP3) is a carrier-type transport protein belonging to the ABC transporters. In this study, we investigated the safety and immunogenicity of a MRP3-derived peptide (MRP3765) as a vaccine and characterized the MRP3-specific T cell responses induced. Twelve hepatocellular carcinoma (HCC) patients treated with hepatic arterial infusion chemotherapy (HAIC) were enrolled. The MRP3-derived peptide was emulsified in incomplete Freund\u27s adjuvant and administered via subcutaneous immunization three times weekly. No serious adverse drug reactions to the peptide vaccine were observed, and the vaccination was well tolerated. The vaccination induced MRP3-specific immunity in 72.7% of the patients. In a phenotypic analysis, the largest post-vaccinated increase in MRP3-specific T cells was due to an increase in cells with the effector memory phenotype. Among the 12 patients, one patient showed a partial response, nine showed a stable disease, and two showed a progressive disease. The median overall survival time was 14.0 months. In conclusion, the safety, effects of immune boosting, and possible prolongation of overall survival by the MRP3-derived peptide demonstrate the potential of the peptide to provide clinical benefit in HCC patients. © 2015

Ripe Tomato Saponin Esculeoside A and Sapogenol Esculeogenin A Suppress CD4+ T Lymphocyte Activation by Modulation of Th2/Th1/Treg Differentiation

We report that esculeoside A (EsA), a glycoside and a major component in ripe tomato fruit, ameliorated experimental dermatitis in mice. However, the underlying immunologic molecular mechanisms are unknown. The present study examined its underlying immune nutrition mechanism using concanavalin A (ConA)-blast mouse splenocyte primary culture. We found that EsA and its sapogenol esculeogenin A (Esg-A) concentration-dependently suppressed T-lymphoproliferation using CFSE-labeled flow-cytometry and water-soluble tetrazolium (WST) assay. Using ELISA and q-PCR methods, EsA/Esg-A showed profound decreases in T helper 2 (Th2)-relevant interleukin-4 (IL-4) secretion and mRNA expression, and GATA3 expression. Moreover, EsA/Esg-A suppressed CD4+ T-lymphocyte activation by decreasing IL-2 secretion and mRNA expression and CD25+ cell proportion. Further, EsA/Esg-A alleviated Treg suppressive activity by reducing IL-10 secretion, Foxp3 mRNA expression, and cell numbers. We suggest the immune nutrition function by tomato component, and highlight that EsA/Esg-A are capable of reducing CD4+ T-lymphocyte activation via a reduction in Th2-lymphocyte activity by modulation of Th2/Th1/Treg subunit differentiation