Regulation of DNA-PK activity promotes the progression of TNBC via enhancing the immunosuppressive function of myeloid-derived suppressor cells.

Abstract

DNA-dependent protein kinase (DNA-PK) is engaged in DNA damage repair and is significantly expressed in triple negative breast cancer (TNBC). Inhibiting DNA-PK to reduce DNA damage repair provides a possibility of tumor treatment. NU7441, a DNA-PK inhibitor, can regulate the function and differentiation of CD4+ T cells and effectively enhance immunogenicity of monocyte-derived dendritic cells. However, the effect of NU7441 on the tumor progression activity of immunosuppressive myeloid-derived suppressor cells (MDSCs) in TNBC remains unclear. In this study, we found that NU7441 alone significantly increased tumor growth in 4T1 (a mouse TNBC cell line) tumor-bearing mice. Bioinformatics analysis showed that DNA-PK and functional markers of MDSCs (iNOS, Arg1, and IDO) tended to coexist in breast cancer patients. The mutations of these genes were significantly correlated with lower survival in breast cancer patients. Moreover, NU7441 significantly decreased the percentage of MDSCs in peripheral blood mononuclear cells (PBMCs), spleen and tumor, but enhanced the immunosuppressive function of splenic MDSCs. Furthermore, NU7441 increased MDSCs' DNA-PK and pDNA-PK protein levels in PBMCs and in the spleen and increased DNA-PK mRNA expression and expression of MDSCs functional markers in splenic MDSCs from tumor-bearing mice. NU7441 combined with gemcitabine reduced tumor volume, which may be because gemcitabine eliminated the remaining MDSCs with enhanced immunosuppressive ability. These findings highlight that the regulation of DNA-PK activity by NU7441 promotes TNBC progression via enhancing the immunosuppressive function of MDSCs. Moreover, NU7441 combined with gemcitabine offers an efficient therapeutic approach for TNBC and merits deeper investigation.