Department of Microbiology and Immunology, Institute of Biosciences, São Paulo State University, Botucatu, SP, Brazil.
Cell Oncol (Dordr). 2011 Apr;34(2):97-106. doi: 10.1007/s13402-010-0005-5. Epub 2011 Jan 20.
We have recently reported that chemotherapeutic agents in ultra low noncytotoxic concentrations may block the ability of tumor cells to suppress functional activation of dendritic cells (DCs).
HCT-116 human colon cancer cells were treated with 0.5 nM paclitaxel (PAC) or 2 nM doxorubicin (DOX) with the aim of defining the immunogenic changes induced by ultra low noncytotoxic concentrations of antineoplastic chemotherapeutic agents. Genetic alterations were screened by DNA microarray that revealed increased expression of genes involved in antigen processing and presentation, including the heat-shock protein, calmodulin, and proteasome 26 genes. As the proteins encoded by these genes are involved in the cytosolic route of antigen processing machinery, we next evaluated whether PAC and DOX in noncytotoxic concentrations changed expression of MHC class I antigen processing machinery (APM) components in three different colon cancer cell lines.
Our results showed that PAC and DOX increased the intracellular expression of APM proteins, including calmodulin, LMP2, LMP7, TAP1 and tapasin. The biological significance of modulation of antigen processing and presentation proteins in tumor cells by ultra low nontoxic concentrations of chemotherapeutic drugs was revealed when non-treated and treated tumor cells were used as a source of tumor antigens for the generation of tumor-specific cytotoxic T cells (CTLs) in vitro. We demonstrated that (i) DCs that engulf tumor cells pretreated with noncytotoxic concentrations of chemotherapeutic agents induced CTLs with a higher cytotoxic potential than DCs loaded with nontreated tumor cells, and (ii) CTLs induced by tumor lysate-pulsed DCs killed live tumor cells more efficiently if these tumor cells were pretreated with noncytotoxic concentrations of chemotherapeutic drugs.
These results demonstrate that chemomodulation of human tumor cells with noncytotoxic concentrations of chemotherapeutic agents increases tumor immunogenicity and results in the generation of more efficient DC vaccines and CTLs, which can be used for cell-based anticancer immunotherapies.
我们最近报道称，低浓度的化疗药物可能会阻断肿瘤细胞抑制树突状细胞（DC）功能激活的能力。
用 0.5 nM 紫杉醇（PAC）或 2 nM 多柔比星（DOX）处理 HCT-116 人结肠癌细胞，以确定低浓度非细胞毒性的抗肿瘤化疗药物诱导的免疫原性变化。通过 DNA 微阵列筛选遗传改变，发现参与抗原加工和呈递的基因表达增加，包括热休克蛋白、钙调蛋白和蛋白酶体 26 基因。由于这些基因编码的蛋白参与抗原加工机制的细胞质途径，我们接下来评估了低浓度非细胞毒性的 PAC 和 DOX 是否改变了三种不同结肠癌细胞系中 MHC Ⅰ类抗原加工机制（APM）成分的表达。
我们的结果表明，PAC 和 DOX 增加了 APM 蛋白的细胞内表达，包括钙调蛋白、LMP2、LMP7、TAP1 和 tapasin。当未处理和处理的肿瘤细胞被用作体外产生肿瘤特异性细胞毒性 T 细胞（CTL）的肿瘤抗原来源时，低浓度无毒化疗药物对肿瘤细胞中抗原加工和呈递蛋白的调节的生物学意义得到了揭示。我们证明了（i）用低浓度化疗药物预处理的肿瘤细胞吞噬的树突状细胞诱导的 CTL 比负载未处理肿瘤细胞的树突状细胞具有更高的细胞毒性潜力，以及（ii）用肿瘤裂解物脉冲处理的 DC 诱导的 CTL 如果这些肿瘤细胞用低浓度的化疗药物预处理，则能更有效地杀伤活肿瘤细胞。
这些结果表明，用低浓度化疗药物对人肿瘤细胞进行化学调节可增加肿瘤免疫原性，并产生更有效的树突状细胞疫苗和 CTL，可用于基于细胞的抗癌免疫治疗。
