title: TLR9 agonists oppositely modulate DNA repair genes in tumor versus immune cells and enhance chemotherapy effects.
abstract: Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN) are a Toll-like receptor 9 (TLR9) agonist that can enhance the antitumor 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 data sets 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 downregulation of DNA repair genes in tumors. Microarray analyses of human IGROV-1 ovarian carcinoma xenografts in mice treated intraperitoneally with CpG-ODN confirmed in silico findings. When combined with the DNA-damaging drug cisplatin, CpG-ODN significantly increased the life span of mice compared with individual treatments. In contrast, CpG-ODN led to an upregulation of genes involved in DNA repair in immune cells. Cisplatin-treated patients with ovarian carcinoma as well as anthracycline-treated patients with breast cancer who are classified as "CpG-like" for the level of expression of CpG-ODN modulated DNA repair genes have a better outcome than 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.
authors: Department of Human Morphology and Biomedical Sciences Città Studi, Università degli Studi di Milano, Italy.
authors: Michele
authors: M
authors: Sommariva
authors: Loris
authors: L
authors: De Cecco
authors: Michelandrea
authors: M
authors: De Cesare
authors: Lucia
authors: L
authors: Sfondrini
authors: Sylvie
authors: S
authors: Ménard
authors: Cecilia
authors: C
authors: Melani
authors: Domenico
authors: D
authors: Delia
authors: Nadia
authors: N
authors: Zaffaroni
authors: Graziella
authors: G
authors: Pratesi
authors: Valentina
authors: V
authors: Uva
authors: Elda
authors: E
authors: Tagliabue
authors: Andrea
authors: A
authors: Balsari
mesh_terms: D000818:Animals; D018943:Anthracyclines / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000627:therapeutic use; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics; D013154:Spleen / Q000187:drug effects* / Q000276:immunology; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018943:Anthracyclines; D000970:Antineoplastic Agents; C408982:CPG-oligonucleotide; D009838:Oligodeoxyribonucleotides; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D002945:Cisplatin