Dual activation of Toll-like receptors 7 and 9 impairs the efficacy of antitumor vaccines in murine models of metastatic breast cancer

• Published in: Journal of cancer research and clinical oncology 2017-09, Vol.143 (9), p.1713-1732
• Main Authors: Moreno Ayala, Mariela A., Gottardo, María Florencia, Gori, María Soledad, Nicola Candia, Alejandro Javier, Caruso, Carla, De Laurentiis, Andrea, Imsen, Mercedes, Klein, Slobodanka, Bal de Kier Joffé, Elisa, Salamone, Gabriela, Castro, Maria G., Seilicovich, Adriana, Candolfi, Marianela
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - therapy; Adjuvants, Immunologic - pharmacology; Animal models; Animals; Antitumor activity; Bone cancer; Bone marrow; Bone marrow transplantation; Breast cancer; Breast Neoplasms - therapy; Cancer Research; Cancer vaccines; Cancer Vaccines - immunology; Cancer Vaccines - pharmacology; Cell activation; CpG islands; Dendritic cells; Dendritic Cells - immunology; Dioxygenase; Feedback; Female; Gene expression; Hematology; Humans; Immune system; Immunological memory; Internal Medicine; Medicine; Medicine & Public Health; Metastases; Metastasis; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; NF-κB protein; Nitric oxide; Nitric-oxide synthase; Oncology; Original Article – Cancer Research; Peripheral blood; Rodents; TLR7 protein; TLR9 protein; Toll-Like Receptor 7 - agonists; Toll-Like Receptor 9 - agonists; Toll-like receptors; Vaccines
• ISSN: 0171-5216; 1432-1335
• DOI: 10.1007/s00432-017-2421-7

Purpose Since combination of Toll-like receptor (TLR) ligands could boost antitumor immunity, we evaluated the efficacy of dendritic cell (DC) vaccines upon dual activation of TLR9 and TLR7 in breast cancer models. Methods DCs were generated from mouse bone marrow or peripheral blood from healthy human donors and stimulated with CpG1826 (mouse TLR9 agonist), CpG2006 or IMT504 (human TLR9 agonists) and R848 (TLR7 agonist). Efficacy of antitumor vaccines was evaluated in BALB/c mice bearing metastatic mammary adenocarcinomas. Results CpG-DCs improved the survival of tumor-bearing mice, reduced the development of lung metastases and generated immunological memory. However, dual activation of TLRs impaired the efficacy of DC vaccines. In vitro, we found that R848 inhibited CpG-mediated maturation of murine DCs. A positive feedback loop in TLR9 mRNA expression was observed upon CpG stimulation that was inhibited in the presence of R848. Impaired activation of NF-κB was detected when TLR9 and TLR7 were simultaneously activated. Blockade of nitric oxide synthase (NOS) and indoleamine-pyrrole-2,3-dioxygenase (IDO) improved the activation of CpG-DCs. When we evaluated the effect of combined activation of TLR9 and TLR7 in human DCs, we found that R848 induced robust DC activation that was inhibited by TLR9 agonists. Conclusions These observations provide insight in the biology of TLR9 and TLR7 crosstalk and suggest caution in the selection of agonists for multiple TLR stimulation. Blockade of NOS and IDO could improve the maturation of antitumor DC vaccines. R848 could prove a useful adjuvant for DC vaccines in human patients.