Chemotherapeutics and radiation stimulate MHC class i expression through elevated interferon-beta signaling in breast cancer cells

Shan Wan, Sidney Pestka, Ronald G. Jubin, Yi Lisa Lyu, Yu Chen Tsai, Leroy-Fong Liu

研究成果: 雜誌貢獻文章

86 引文 (Scopus)

摘要

Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT), a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I) expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β) and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-naïve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1) or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine) similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through T cell cytotoxicity during metronomic chemotherapy, as well as increased efficacy of combined chemo- (or radio-)/immuno-therapy.

原文英語
文章編號e32542
期刊PLoS One
7
發行號3
DOIs
出版狀態已發佈 - 三月 1 2012
對外發佈Yes

指紋

interferon-beta
Topotecan
Interferon-beta
major histocompatibility complex
breast neoplasms
Interferons
interferons
Cells
Major Histocompatibility Complex
Radiation
Breast Neoplasms
cells
Conditioned Culture Medium
immunotherapy
Interferon alpha-beta Receptor
Cytokines
Type I DNA Topoisomerase
Chemotherapy
T-cells
Vinblastine

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

引用此文

Chemotherapeutics and radiation stimulate MHC class i expression through elevated interferon-beta signaling in breast cancer cells. / Wan, Shan; Pestka, Sidney; Jubin, Ronald G.; Lyu, Yi Lisa; Tsai, Yu Chen; Liu, Leroy-Fong.

於: PLoS One, 卷 7, 編號 3, e32542, 01.03.2012.

研究成果: 雜誌貢獻文章

Wan, Shan ; Pestka, Sidney ; Jubin, Ronald G. ; Lyu, Yi Lisa ; Tsai, Yu Chen ; Liu, Leroy-Fong. / Chemotherapeutics and radiation stimulate MHC class i expression through elevated interferon-beta signaling in breast cancer cells. 於: PLoS One. 2012 ; 卷 7, 編號 3.
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abstract = "Low doses of anticancer drugs have been shown to enhance antitumor immune response and increase the efficacy of immunotherapy. The molecular basis for such effects remains elusive, although selective depletion of T regulatory cells has been demonstrated. In the current studies, we demonstrate that topotecan (TPT), a topoisomerase I-targeting drug with a well-defined mechanism of action, stimulates major histocompatibility complex class I (MHC I) expression in breast cancer cells through elevated expression/secretion of interferon-β (IFN-β) and activation of type I IFN signaling. First, we show that TPT treatment elevates the expression of both total and cell-surface MHC I in breast cancer cells. Second, conditioned media from TPT-treated breast cancer ZR-75-1 cells induce elevated expression of cell-surface MHC I in drug-na{\"i}ve recipient cells, suggesting the involvement of cytokines and/or other secreted molecules. Consistently, TPT-treated cells exhibit elevated expression of multiple cytokines such as IFN-β, TNF-α, IL-6 and IL-8. Third, either knocking down the type I interferon receptor subunit 1 (IFNAR1) or addition of neutralizing antibody against IFN-β results in reduced MHC I expression in TPT-treated cells. Together, these results suggest that TPT induces increased IFN-β autocrine/paracrine signaling through type I IFN receptor, resulting in the elevated MHC I expression in tumor cells. Studies have also demonstrated that other chemotherapeutic agents (e.g. etoposide, cisplatin, paclitaxel and vinblastine) similarly induce increased IFN-β secretion and elevated MHC I expression. In addition, conditioned media from γ-irradiated donor cells are shown to induce IFN-β-dependent MHC I expression in unirradiated recipient cells. In the aggregate, our results suggest that many cancer therapeutics induce elevated tumor antigen presentation through MHC I, which could represent a common mechanism for enhanced antitumor immune response through T cell cytotoxicity during metronomic chemotherapy, as well as increased efficacy of combined chemo- (or radio-)/immuno-therapy.",
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