Okuzawa Masaaki, Shinohara Hisashi, Kobayashi Toshihiro, Iwamoto Mitsuhiko, Toyoda Masao, Tanigawa Nobuhiko
Department of General and Gastroenterological Surgery, Osaka Medical College, 2-7 Daigaku-cho, Takatsuki 569-8686, Japan.
Int J Oncol. 2002 Jun;20(6):1189-95.
Dendritic cells (DC) are the most potent antigen-presenting cells that induce specific anti-tumor immunity. To obtain potent efficacy of immunotherapy using infusion of activated DC, it is necessary to overcome defective function of DC in tumor-bearing patients. We examined whether the treatment with PSK, a biological response modifier derived from Basidiomycetes, could allow DC to avoid inhibition of functional maturation by tumor-derived factors in vitro. CD14+ monocyte-derived DC were generated by stimulating with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4 in the presence or absence of PSK (100 microg/ml), by exposure to a tumor culture supernatant (TSN) of MKN-45P human gastric cancer cells. TSN-exposed DC were not effective in inducing cytotoxic T lymphocyte-mediated growth inhibition of target HT29 human colon cancer cells. In contrast, the presence of PSK significantly resuscitated the defective cytotoxicity. This beneficial outcome was accompanied by an increase in phagocytic activity as measured by fluorescein isothiocyanate-conjugated dextran, expression of CD83 (maturation-specific phenotype), overexpression of a CD86 co-stimulatory molecule, preserved production of IL-12 that plays a key role in the induction of Th1-type immune regulations, and protection against TSN-induced apoptosis of DC. These results demonstrated that PSK overcomes defective maturation of DC exposed to tumor-derived factors in vitro, and suggest the efficacy of PSK in DC-based immunotherapy in cancer patients.
树突状细胞（DC）是诱导特异性抗肿瘤免疫的最有效的抗原呈递细胞。为了通过输注活化的DC获得免疫治疗的强效疗效，有必要克服荷瘤患者中DC的功能缺陷。我们研究了来源于担子菌的生物反应调节剂PSK的治疗是否能使DC在体外避免肿瘤衍生因子对功能成熟的抑制。在存在或不存在PSK（100微克/毫升）的情况下，通过用粒细胞巨噬细胞集落刺激因子和白细胞介素（IL）-4刺激，由CD14+单核细胞衍生的DC通过暴露于MKN-45P人胃癌细胞的肿瘤培养上清液（TSN）而产生。暴露于TSN的DC在诱导细胞毒性T淋巴细胞介导的对靶标HT29人结肠癌细胞的生长抑制方面无效。相比之下，PSK的存在显著恢复了缺陷的细胞毒性。这一有益结果伴随着吞噬活性的增加（通过异硫氰酸荧光素偶联的葡聚糖测量）、CD83（成熟特异性表型）的表达、CD86共刺激分子的过表达、在Th1型免疫调节诱导中起关键作用的IL-12的持续产生以及对TSN诱导的DC凋亡的保护。这些结果表明，PSK克服了体外暴露于肿瘤衍生因子的DC的成熟缺陷，并提示了PSK在癌症患者基于DC的免疫治疗中的疗效。
