Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice
Application of paclitaxel in low non-cytotoxic doses supports vaccination with melanoma antigens in normal mice
复制标题
DOI：
10.3109/1547691x.2012.655343
复制
发表时间：
2012-07-01
影响因子：
3.3
通讯作者：
Umansky, Viktor
中科院分区：
文献类型：
--
作者：
Sevko, Alexandra;Kremer, Veronika;Umansky, Viktor
以超低、非细胞毒性剂量施用的化学治疗剂如紫杉醇先前显示在小鼠可移植肿瘤模型中接种疫苗后刺激树突状细胞活性和抗肿瘤免疫应答。然而，这些改变的机制-称为化学免疫调节或化学调节-仍然不清楚。本研究调查了以超低、无细胞毒性剂量施用的紫杉醇对健康C57 BL/6小鼠用酪氨酸酶相关蛋白（TRP）-2衍生肽作为模型黑素瘤抗原免疫的效率的影响。使用IFN γ ELISPOT测定，发现与单独接种疫苗的水平相比，与肽接种疫苗组合施用1 mg紫杉醇/kg强烈增加了TRP-2特异性脾T细胞的频率。这与调节性T细胞（T-reg）和未成熟骨髓细胞（称为健康小鼠中骨髓源性抑制细胞[MDSC]的对应物）水平的显著降低有关。发现潜在免疫抑制细胞的这种损伤与骨髓和脾脏中效应CD 8+和CD 4 + T细胞的量的强烈增加相关。此外，在紫杉醇治疗的小鼠中，观察到骨髓中自然杀伤（NK）细胞数量及其产生IFN γ的能力显著增加。此外，淋巴结中的NK-T细胞水平也增加。这表明，以超低、无细胞毒性剂量施用的紫杉醇可能通过中和荷瘤宿主中的免疫抑制性T-reg和MDSC群体而潜在地增强抗肿瘤疫苗接种的功效。
Chemotherapeutic agents such as paclitaxel applied in ultra-low, non-cytotoxic doses were previously shown to stimulate dendritic cell activity and anti-tumor immune responses upon vaccination in mouse transplantable tumor models. However, the mechanisms of these alterations-termed chemoimmunomodulation or chemomodulation-are still not clear. This study investigated the effect of paclitaxel applied in ultra-low, non-cytotoxic doses on the efficiency of immunization of healthy C57BL/6 mice with the peptide derived from tyrosinase related protein (TRP)-2 as a model melanoma antigen. Using an IFN gamma ELISPOT assay, it was found that administration of 1 mg paclitaxel/kg in combination with the peptide vaccination strongly increased the frequencies of TRP-2 specific spleen T-cells as compared to levels due to the vaccination alone. This was associated with a significant decrease in the levels of regulatory T-cells (T-reg) and immature myeloid cells (known as a counterpart of myeloid derived suppressor cells [MDSC] in healthy mice). Such impairments of potential immunosuppressive cells were found to correlate with a strong increase in the amount of effector CD8+ and CD4+ T-cells in the bone marrow and spleen. Furthermore, in paclitaxel-treated mice, a significant augmentation of natural killer (NK) cell numbers in the bone marrow and their ability to produce IFN gamma were observed. In addition, the level of NK-T-cells in the lymph nodes was also increased. It is suggested that paclitaxel applied in ultra- low, non-cytotoxic doses may potentially enhance the efficacy of anti-tumor vaccinations by neutralizing immunosuppressive T-reg and MDSC populations in tumor-bearing hosts.