Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer

Xiaolin Hu, Kankana Bardhan, Amy V. Paschall, Dafeng Yang, Jennifer L Waller, Mary Anne Park, Asha Nayak, Thomas A. Samuel, Scott I. Abrams, Kebin Liu

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that accumulate in response to tumor progression. Compelling data from mouse models and human cancer patients showed that tumor-induced inflammatory mediators induce MDSC differentiation. However, the mechanisms underlying MDSC persistence is largely unknown. Here, we demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis as compared with myeloid cells with the same phenotypes from tumor-free mice. Consistent with the decreased apoptosis, cell surface Fas receptor decreased significantly in tumor-induced MDSCs. Screening for changes of key apoptosis mediators downstream the Fas receptor revealed that expression levels of IRF8 and Bax are diminished, whereas expression of Bcl-xL is increased in tumor-induced MDSCs. We further determined that IRF8 binds directly to Bax and Bcl-x promoter in primary myeloid cells in vivo, and IRF8-deficient MDSC-like cells also exhibit increased Bcl-xL and decreased Bax expression. Analysis of CD69 and CD25 levels revealed that cytotoxic T lymphocytes (CTLs) are partially activated in tumor-bearing hosts. Strikingly, FasL but not perforin and granzymes were selectively activated in CTLs in the tumor-bearing host. ABT-737 significantly increased the sensitivity of MDSCs to Fas-mediated apoptosis in vitro. More importantly, ABT-737 therapy increased MDSC spontaneous apoptosis and decreased MDSC accumulation in tumor-bearing mice. Our data thus determined that MDSCs use down-regulation of IRF8 to alter Bax and Bcl-xL expression to deregulate the Fas-mediated apoptosis pathway to evade elimination by host CTLs. Therefore, targeting Bcl-xL is potentially effective in suppression of MDSC persistence in cancer therapy.

Original languageEnglish (US)
Pages (from-to)19103-19115
Number of pages13
JournalJournal of Biological Chemistry
Volume288
Issue number26
DOIs
StatePublished - Jun 28 2013

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Deregulation
Tumors
Bearings (structural)
Apoptosis
Neoplasms
T-cells
CD95 Antigens
Cytotoxic T-Lymphocytes
Myeloid Cells
Myeloid-Derived Suppressor Cells
Granzymes
Perforin
Screening
Cell Surface Receptors
Cell Differentiation
Down-Regulation

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer. / Hu, Xiaolin; Bardhan, Kankana; Paschall, Amy V.; Yang, Dafeng; Waller, Jennifer L; Park, Mary Anne; Nayak, Asha; Samuel, Thomas A.; Abrams, Scott I.; Liu, Kebin.

In: Journal of Biological Chemistry, Vol. 288, No. 26, 28.06.2013, p. 19103-19115.

Research output: Contribution to journalArticle

Hu, Xiaolin ; Bardhan, Kankana ; Paschall, Amy V. ; Yang, Dafeng ; Waller, Jennifer L ; Park, Mary Anne ; Nayak, Asha ; Samuel, Thomas A. ; Abrams, Scott I. ; Liu, Kebin. / Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer. In: Journal of Biological Chemistry. 2013 ; Vol. 288, No. 26. pp. 19103-19115.
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AU - Hu, Xiaolin

AU - Bardhan, Kankana

AU - Paschall, Amy V.

AU - Yang, Dafeng

AU - Waller, Jennifer L

AU - Park, Mary Anne

AU - Nayak, Asha

AU - Samuel, Thomas A.

AU - Abrams, Scott I.

AU - Liu, Kebin

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AB - Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that accumulate in response to tumor progression. Compelling data from mouse models and human cancer patients showed that tumor-induced inflammatory mediators induce MDSC differentiation. However, the mechanisms underlying MDSC persistence is largely unknown. Here, we demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis as compared with myeloid cells with the same phenotypes from tumor-free mice. Consistent with the decreased apoptosis, cell surface Fas receptor decreased significantly in tumor-induced MDSCs. Screening for changes of key apoptosis mediators downstream the Fas receptor revealed that expression levels of IRF8 and Bax are diminished, whereas expression of Bcl-xL is increased in tumor-induced MDSCs. We further determined that IRF8 binds directly to Bax and Bcl-x promoter in primary myeloid cells in vivo, and IRF8-deficient MDSC-like cells also exhibit increased Bcl-xL and decreased Bax expression. Analysis of CD69 and CD25 levels revealed that cytotoxic T lymphocytes (CTLs) are partially activated in tumor-bearing hosts. Strikingly, FasL but not perforin and granzymes were selectively activated in CTLs in the tumor-bearing host. ABT-737 significantly increased the sensitivity of MDSCs to Fas-mediated apoptosis in vitro. More importantly, ABT-737 therapy increased MDSC spontaneous apoptosis and decreased MDSC accumulation in tumor-bearing mice. Our data thus determined that MDSCs use down-regulation of IRF8 to alter Bax and Bcl-xL expression to deregulate the Fas-mediated apoptosis pathway to evade elimination by host CTLs. Therefore, targeting Bcl-xL is potentially effective in suppression of MDSC persistence in cancer therapy.

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