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.

TLR9-agonists oppositely modulate DNA-repair genes in tumor versus immune cells and enhance chemotherapy effects / M. Sommariva, L. De Cecco, M. De Cesare, L. Sfondrini, S. Mènard, C. Melani, D. Delia, N. Zaffaroni, G. Pratesi, V. Uva, E. Tagliabue, A. Balsari. - In: CANCER RESEARCH. - ISSN 0008-5472. - 71:20(2011 Oct 15), pp. 6382-6390. [10.1158/0008-5472.CAN-11-1285]

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

M. Sommariva
Primo
;
L. Sfondrini;V. Uva;A. Balsari
Ultimo
2011

Abstract

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.
toll-like receptor-9; CpG-oligodeoxynucleotides; cancer-therapy; in-vivo; expression; PF-3512676; activation; signatures; carcinoma; responses
Settore MED/04 - Patologia Generale
Settore BIO/17 - Istologia
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/162734
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