Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells.
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 t...
Guardado en:
| Autores principales: | , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Public Library of Science (PLoS)
2012
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/4d3adabd17e144ed8665bc735940c869 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:4d3adabd17e144ed8665bc735940c869 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:4d3adabd17e144ed8665bc735940c8692021-11-18T07:26:17ZChemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells.1932-620310.1371/journal.pone.0032542https://doaj.org/article/4d3adabd17e144ed8665bc735940c8692012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22396773/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203Low 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.Shan WanSidney PestkaRonald G JubinYi Lisa LyuYu-Chen TsaiLeroy F LiuPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 3, p e32542 (2012) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q Shan Wan Sidney Pestka Ronald G Jubin Yi Lisa Lyu Yu-Chen Tsai Leroy F Liu Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. |
| description |
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. |
| format |
article |
| author |
Shan Wan Sidney Pestka Ronald G Jubin Yi Lisa Lyu Yu-Chen Tsai Leroy F Liu |
| author_facet |
Shan Wan Sidney Pestka Ronald G Jubin Yi Lisa Lyu Yu-Chen Tsai Leroy F Liu |
| author_sort |
Shan Wan |
| title |
Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. |
| title_short |
Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. |
| title_full |
Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. |
| title_fullStr |
Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. |
| title_full_unstemmed |
Chemotherapeutics and radiation stimulate MHC class I expression through elevated interferon-beta signaling in breast cancer cells. |
| title_sort |
chemotherapeutics and radiation stimulate mhc class i expression through elevated interferon-beta signaling in breast cancer cells. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/4d3adabd17e144ed8665bc735940c869 |
| work_keys_str_mv |
AT shanwan chemotherapeuticsandradiationstimulatemhcclassiexpressionthroughelevatedinterferonbetasignalinginbreastcancercells AT sidneypestka chemotherapeuticsandradiationstimulatemhcclassiexpressionthroughelevatedinterferonbetasignalinginbreastcancercells AT ronaldgjubin chemotherapeuticsandradiationstimulatemhcclassiexpressionthroughelevatedinterferonbetasignalinginbreastcancercells AT yilisalyu chemotherapeuticsandradiationstimulatemhcclassiexpressionthroughelevatedinterferonbetasignalinginbreastcancercells AT yuchentsai chemotherapeuticsandradiationstimulatemhcclassiexpressionthroughelevatedinterferonbetasignalinginbreastcancercells AT leroyfliu chemotherapeuticsandradiationstimulatemhcclassiexpressionthroughelevatedinterferonbetasignalinginbreastcancercells |
| _version_ |
1718423473397694464 |