Expression of multidrug resistance-associated protein 3 and cytotoxic T cell responses in patients with hepatocellular carcinoma

Mizukoshi, Eishiro; Honda, Masao; Arai, Kuniaki; Yamashita, Tatsuya; Nakamoto, Yasunari

doi:10.1016/j.jhep.2008.05.012

Cited by 29 publications

(25 citation statements)

References 29 publications

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“…Patients with hepatocellular carcinoma generate cytotoxic T cell responses against the MDR gene product MRP3 (Mizukoshi et al, 2008) suggesting it as an immune target for immunotherapy.…”

Section: Specific Therapies Targeting Mdr+ Cancer Cellsmentioning

confidence: 99%

Immunotherapy: A useful strategy to help combat multidrug resistance

Curiel¹

2012

Drug Resistance Updates

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Multidrug resistance (MDR) renders cancer cells relatively invulnerable to treatment with many standard cytotoxic anti-cancer agents. Cancer immunotherapy could be an important adjunct other strategies to treat MDR positive cancers, as resistance to immunotherapy generally is unrelated to mechanisms of resistance to cytotoxic agents. Immunotherapy to combat MDR positive tumors could use any of the following strategies: direct immune attack against MDR positive cells, using MDR as an immune target to deliver cytotoxic agents, capitalization on other immune properties of MDR positive cells, or conditional immunotoxins expressed under MDR control. Additional insights into the immunogenic potential of some cytotoxic agents can also be brought to bear on these strategies. This review will highlight key concepts in cancer immunotherapy and illustrate immune principles and strategies that have been or could be used to help destroy MDR positive tumor cells, either alone or in rational combinations.

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“…Patients with hepatocellular carcinoma generate cytotoxic T cell responses against the MDR gene product MRP3 (Mizukoshi et al, 2008) suggesting it as an immune target for immunotherapy.…”

Section: Specific Therapies Targeting Mdr+ Cancer Cellsmentioning

confidence: 99%

Immunotherapy: A useful strategy to help combat multidrug resistance

Curiel¹

2012

Drug Resistance Updates

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“…Together with MPR2, these are components of the multidrug resistance phenotype (21) and its upregulation has been confirmed in choriocarcinoma and cervical cancer (22). The protein encoded by this gene is a tumor-associated antigen in HCC recognized by cytotoxic T cells and has been suggested as an immunogenic target for HCC immunotherapy (23).…”

Section: Discussionmentioning

confidence: 96%

Analysis of gene expression profiles as a tool to uncover tumor markers of liver cancer progression in a rat model

et al. 2014

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Establishing a transcriptomic profile of human hepatocellular liver cancer (HCC) progression is a complex undertaking. A rat model of HCC was employed to develop a transcriptomic profile. Using three interventions, preneoplastic lesions appeared after 30 days and they progressed to HCC by 9 months. Preneoplastic and cancer lesions were characterized for transcriptomic analysis, and RNA from total liver homogenates was obtained at 1, 7, 11 and 16 days after the initiation treatment. RNA from dissected persistent preneoplastic lesions, adjacent tissue or cancer tissue was used for 30 days, and 5, 9, 12 and 18 months. The GeneChip Rat Exon 1.0 ST arrays, Partek software and an Affymetrix console were employed for these analyses. was differentially expressed at each time point, from the initial period, through the preneoplastic evolution period and until the end of cancer progression period. Twelve differentially expressed genes common to the preneoplastic evolution and to the cancer progression period were detected, which included. Validation of the microarrays was confirmed by reverse transcription-quantitative polymerase chain reaction of six genes, including and. Of note, the proteins of these two genes are associated with the multidrug response complex, and evasion of immune surveillance and negative regulation of T cell proliferation. This model is useful for identifying candidate genes, and to validate them with regards to determining their relevance in rat HCC progression.

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“…These results are favorable for anticancer immunotherapy because the antigenspecific T-cell-mediated immune response could be detected without in vitro stimulation. As for frequency, GPC3-specific CTLs were detectable in ~40% of HCC patients, whereas AFP-, human telomerase reverse transcriptase (hTERT)-, and multidrug resistance-associated protein 3 (MRP3)-specific CTLs have been detected in 5-20, 6-12, and 14-21% of HCC patients with a single epitope peptide, respectively (26)(27)(28). As for tumor stages, a GPC3-specific immune response is frequently detected even in the early stages (24), whereas AFP-specific CTLs are more frequently detected in patients with advanced HCC (26).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we obtained the result that the presence of GPC3-specific CTLs in PBMCs potentially had a positive correlation with GPC3 expression in tumor tissue, but the correlation was not statistically significant. On the other hand, Mizukoshi et al showed a negative correlation between the frequency of MRP3-specific CTLs and MRP3 expression level (28). Moreover, benavides et al showed that even antigennaïve patients had pre-existing immunity (29).…”

Section: Discussionmentioning

confidence: 99%

Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

et al. 2011

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Abstract. Glypican-3 (GPC3), a carcinoembryonic antigen, is an ideal target for anticancer immunotherapy against hepatocellular carcinoma (HCC). In this study, we attempted to compare the induction of the GPC3-specific T-cell-mediated immune response after locoregional therapies in HCC patients and tumor-bearing mice. Twenty-seven HCC patients treated with locoregional therapies, including radiofrequency ablation (RFA), surgical resection and transcatheter arterial chemoembolization (TACE), were prospectively enrolled in this study. Additionally, we performed RFA experiments using a mouse model. GPC3-specific T-cell response was investigated pretreatment and post-treatment by an interferon-γ enzyme-linked immunospot assay using peripheral blood mononuclear cells from HCC patients and lymph node cells from tumor-bearing mice. Circulating GPC3-specific cytotoxic T lymphocytes (CTLs) were increased in 5 of 9 patients after RFA and in 4 of 9 patients after TACE, but in only 1 of 9 patients after surgical resection. All 7 patients with GPC3-expressing HCCs exhibited an increase in GPC3-specific CTLs after RFA or TACE, whereas none of the 7 patients did after surgical resection. The number of increased GPC3-specific CTLs after RFA was significantly larger than that after surgical resection (P= 0.023). Similarly, the frequency of GPC3-specific CTLs after RFA was significantly greater than that after surgical resection in the mouse model (P=0.049). We validated for the first time the stronger effect on the immune system brought by RFA compared with surgical resection for HCC patients and tumor-bearing mice. Combined treatment of RFA and immunotherapy is a reasonable strategy against HCC. IntroductionHepatocellular carcinoma (HCC) is one of the most common and most serious cancers worldwide (1). Locoregional therapies, including radiofrequency ablation (RFA), surgical resection, and transcatheter arterial chemoembolization (TACE), are recognized as the gold-standard therapies for HCC patients whose cancer lesions are limited to the liver (2). However, the recurrence rate remains quite high despite potentially curative treatment (3,4). The reasons for this are as follows: first, a multicentric new tumor frequently occurs from underlying active hepatitis or cirrhosis and, second, a small tumor undetectable by imaging modalities frequently exists before treatment and would be left untreated (5). Therefore, the establishment of effective adjuvant therapy to prevent recurrence is urgently required, and Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

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Expression of multidrug resistance-associated protein 3 and cytotoxic T cell responses in patients with hepatocellular carcinoma

Cited by 29 publications

References 29 publications

Immunotherapy: A useful strategy to help combat multidrug resistance

Immunotherapy: A useful strategy to help combat multidrug resistance

Analysis of gene expression profiles as a tool to uncover tumor markers of liver cancer progression in a rat model

Radiofrequency ablation for hepatocellular carcinoma induces glypican-3 peptide-specific cytotoxic T lymphocytes

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