Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer

Abstract

Background:The mechanism underlying MDSC persistence in tumor-bearing hosts is elusive. Results: IRF8 is down-regulated in MDSCs, resulting in Fas, Bax, and Bcl-xL deregulation and decreased spontaneous apoptosis. Conclusion: Increased resistance to Fas-mediated apoptosis is at least partially responsible for MDSC accumulation. Significance: Targeting Bcl-xL is potentially an effective approach to suppress MDSCs in cancer therapy.

Pak2 regulates myeloid-derived suppressor cell development in mice

“…47 Respectively decreased and increased levels of Bax and Bcl-xL expression were observed in IRF8-deficient MDSCs from tumor-bearing mice than in myeloid cells with the same phenotypes from tumor-free mice. 43 Downregulation of IRF8 and Bax expression in Pak2-deficient MDSCs is consistent with the finding in MDSCs from tumor-bearing mice 43 and the report that IRF8-KO CD11b 1 primary myeloid cells display lower Bax expression level than WT cells. 23 On the other hand, Pak2-deficient MDSCs, while having reduced IRF8 expression ( Figure 6C-D), had a comparable level of Bcl-xL expression when compared with WT CD11b high Gr1 high PMNs ( Figure 5E).…”

“…Our data are in line with the reported decreased sensitivity of IRF8-deficient MDSCs to spontaneous and Fasmediated apoptosis. 23,43 Collectively, our data demonstrate that loss of Pak2 function results in deregulated intrinsic and extrinsic anti-and pro apoptotic pathways, thus conferring apoptosis resistance to MDSCs.…”

“…41,42 Upregulation of Bcl-xL and downregulation of Bax confers apoptotic resistance to MDSCs and contributes to their persistence in cancer. 43 Significantly lower levels of Bcl2, Bax, and Bak1 expression were observed in Pak2-deficient MDSCs than in WT CD11b shown. *P , .05; ****P , .0001.…”

“…48 Deregulation of the Fas-mediated apoptosis pathway confers increased MDSC resistance to apoptosis in tumor-bearing hosts. 43 Pak2-deficient MDSCs, with diminished IRF8 expression and cell-surface Fas protein levels, display resistance to Fas-FasL-mediated apoptosis ( Figure 5A). Our data are in line with the reported decreased sensitivity of IRF8-deficient MDSCs to spontaneous and Fasmediated apoptosis.…”

“…It mediates myeloid cell apoptosis through upregulation of Bcl-xL 43 and downregulation of Bax 23,43 and Bcl-2. 47 Respectively decreased and increased levels of Bax and Bcl-xL expression were observed in IRF8-deficient MDSCs from tumor-bearing mice than in myeloid cells with the same phenotypes from tumor-free mice.…”