Modulation of HLA class I expression in multidrug-resistant human rhabdomyosarcoma cells.
ABSTRACT An abnormal HLA expression has been detected in some tumors including rhabdomyosarcoma (RMS). Classical cytotoxic treatment of these tumors, the most common childhood soft tissue malignancy, may induce multidrug resistance (MDR) associated with the expression of a 170-kDa membrane-associated glycoprotein (P-glycoprotein). In order to analyse the connection between modulation of HLA expression and the development of the MDR phenotype mediated by P-glycoprotein in RMS, we used three resistant RMS cell lines; two of these resistant cell lines (TE.32.7.DAC and RD-DAC) were established by in vitro exposure to actinomycin D, a drug of choice in the treatment of RMS; the resistant RMS- GR cell line was established from an embryonal RMS tumor after polychemotherapy. Our results showed that all the resistant cell lines showed a significant increase in the expression of HLA class I surface antigens in comparison to drug-sensitive cells. Blockade of P-glycoprotein with verapamil led to a decrease in HLA class I expression in RMS resistant cell lines. However, no modulation of HLA class II expression was observed in any of the three analyzed cell lines. These findings support the hypothesis that the development of resistance mediated by mdr 1/P-glycoprotein, directly influences the expression of HLA class I in RMS cells, inducing to upregulation. This effect may be relevant to the application in RMS of immunotherapy against tumor-associated antigens presented by HLA class I molecules.
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ABSTRACT: Despite dramatic advances in surgical techniques, imaging and adjuvant radiotherapy or chemotherapy, the prognosis for patients with malignant glial tumors remains dismal. Based on the current knowledge regarding immune responses in the healthy CNS and glioma-bearing hosts, this review discusses dendritic cell-based immunotherapeutic approaches for malignant gliomas and the relevance of recent clinical trials and their outcomes. It is now recognized that the CNS is not an immunologically tolerated site and clearance of arising glioma cells is a routine physiologic function of the normal, noncompromised immune system. To escape from immune surveillance, however, clinically apparent gliomas develop complex mechanisms that suppress tumoricidal immune responses. Although the use of dendritic cells for the treatment of glioma patients may be the most appropriate approach, an effective treatment paradigm for these tumors may eventually require the use of several types of treatment. Additionally, given the heterogeneity of this disease process and an immune-refractory tumor cell population, the series use of rational multiple modalities that target disparate tumor characteristics may be the most effective therapeutic strategy to treat malignant gliomas.Expert Review of Neurotherapeutics 08/2005; 5(4):497-508. DOI:10.1586/14737220.127.116.117 · 2.96 Impact Factor
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ABSTRACT: Drug resistance represents a major cause of chemotherapy failure in patients with cancer. The characterization of the molecular pathways involved in drug resistance has provided new targets to circumvent or reverse chemotherapy resistance. Many of these target proteins are often overexpressed in human glioma and have been identified as tumor antigens, which implicate the development of immunotherapy as a therapeutic strategy. Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system and have been demonstrated to stimulate antibody and cell-mediated immune responses against tumor-associated antigens. Ex vivo-generated and tumor antigen-loaded DCs have been successfully introduced to clinical vaccination protocols, which have proven to be feasible and effective in some glioma patients. Most importantly, immunotherapy followed by chemotherapy could significantly increase 2-year survival in malignant glioma patients, which obviously demonstrates that DC vaccination could increase the sensitivity of tumor cells to chemotherapy. This review focuses on recent advances in the identification of tumor-associated antigen in glioma, as well as novel insights into their biological function related to drug resistance. These insights may provide the rationale for a novel strategy of a DC cancer vaccine that sensitizes tumor cells to chemotherapy. In addition, the current research status and the future direction of a DC-based vaccine to treat glioma in animal models and clinical trials will also be discussed.Expert Review of Vaccines 05/2006; 5(2):233-47. DOI:10.1586/14760518.104.22.168 · 4.22 Impact Factor
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ABSTRACT: A major reason chemotherapy fails in cancer treatment is drug resistance. New targets against chemotherapy resistance have been developed with the identification of molecular pathways in drug resistance. These targets are proteins that are highly expressed in human gliomas and are known to be tumor antigens. The immune system produces specialized white blood cells called dendritic cells (DCs). DCs are the most potent antigen-presenting cell of the immune system. DCs have demonstrated the ability to stimulate antibodies and cell-mediated immune responses against tumor antigens. Immunotherapy has emerged as a novel treatment strategy for gliomas with tumor antigens serving as the driving force. Clinical immunotherapy trials for glioma patients using vaccinations made of tumor antigens combined with dendritic cells ex vivo have shown promising results. DC vaccinations may increase sensitivity to chemotherapy, as demonstrated by a significant increase in 2-year survival rates in patients with malignant gliomas who received chemotherapy after immunotherapy (51). The use of DC vaccinations to increase sensitivity of tumor cells to chemotherapy can be rationalized as a novel strategy. Hence, this review will focus on the recent advances in the identification of tumor-associated antigens in gliomas, as well as their biological function related to drug resistance. The current research status and the future direction of DC vaccines to treat glioma in animal models and clinical trials will also be discussed.Clinical neurosurgery 02/2006; 53:345-51.