title: Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, Georgia 30912, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hu
authors.forename: Kankana
authors.initials: K
authors.lastname: Bardhan
authors.forename: Amy V
authors.initials: AV
authors.lastname: Paschall
authors.forename: Dafeng
authors.initials: D
authors.lastname: Yang
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Waller
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Park
authors.forename: Asha
authors.initials: A
authors.lastname: Nayak-Kapoor
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Samuel
authors.forename: Scott I
authors.initials: SI
authors.lastname: Abrams
authors.forename: Kebin
authors.initials: K
authors.lastname: Liu
mesh_terms: D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology; D053181:Caspase 8 / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D050835:Interferon Regulatory Factors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000166:cytology*; D009369:Neoplasms / Q000378:metabolism*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D053181:Caspase 8; D050835:Interferon Regulatory Factors; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019014:fas Receptor; D000099185:Interferon Regulatory Factor-8; C494811:BCL2L1 protein, human
keywords: Apoptosis; Bax; Bcl-2 Family; Fas; Myeloid Cell