TLR9-agonists oppositely modulate DNA-repair genes in tumor versus immune cells and enhance chemotherapy effects

Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN) are a TLR9 agonist that can enhance the anti-tumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models. We hypothesized that the success of these combinations is related to the ability of CpG-ODN to modulate genes involved in DNA-repair. We conducted an in silico analysis of genes implicated in DNA-repair in datasets obtained from murine colon carcinoma cells in mice injected intratumorally with CpG-ODN and from splenocytes in mice treated intraperitoneally with CpG-ODN. CpG-ODN treatment caused down-regulation of DNA-repair genes in tumors. Microarray analyses of human IGROV-1 ovarian carcinoma xenografts in mice treated i.p. with CpG-ODN confirmed in silico findings. When combined with the DNA-damaging drug cisplatin, CpG-ODN significantly increased the lifespan of mice compared to individual treatments. In contrast, CpG-ODN led to an up-regulation of genes involved in DNA-repair in immune cells. Cisplatin-treated ovarian carcinoma patients as well as anthracycline-treated breast cancer patients that are classified as "CpG-like" for the level of expression of CpG-ODN modulated DNA-repair genes have a better outcome when compared to patients classified as "CpG-untreated-like", indicating the relevance of these genes in the tumor cell response to DNA-damaging drugs. Taken together, the findings provide evidence that the tumor microenvironment can sensitize cancer cells to DNA-damaging chemotherapy, thereby expanding the benefits of CpG-ODN therapy beyond induction of a strong immune response.