Toll-like receptor 9 agonist enhances anti-tumor immunity and inhibits tumor-associated immunosuppressive cells numbers in a mouse cervical cancer model following recombinant lipoprotein therapy

Molecular Cancer

Research

Hai-Mei Huang¹  Li-Sheng Chang²  Chiao-Chieh Wu³  Chih-Hsiang Leng³  Yi-Chen Yeh³  Shih-Jen Liu⁴  Hsin-Wei Chen⁴ 

[1] Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan;Institute of Biotechnology and Department of Life Science, National Tsing Hua University, Hsinchu, Taiwan;National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, 35053, Miaoli County, Zhunan Town, Taiwan;National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, 35053, Miaoli County, Zhunan Town, Taiwan;National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, No. 35, Keyan Road, 35053, Miaoli County, Zhunan Town, Taiwan;Graduate Institute of Immunology, China Medical University, Taichung, Taiwan;

关键词: Vaccine;    Innate receptor;    Immunotherapy;    Human papillomavirus;   

DOI  :  10.1186/1476-4598-13-60

 received in 2014-01-15, accepted in 2014-03-12,  发布年份 2014

来源: Springer

【 摘 要 】

BackgroundAlthough cytotoxic T lymphocytes (CTLs) play a major role in eradicating cancer cells during immunotherapy, the cancer-associated immunosuppressive microenvironment often limits the success of such therapies. Therefore, the simultaneous induction of cancer-specific CTLs and reversal of the immunosuppressive tumor microenvironment may be more effectively achieved through a single therapeutic vaccine. A recombinant lipoprotein with intrinsic Toll-like receptor 2 (TLR2) agonist activity containing a mutant form of E7 (E7m) and a bacterial lipid moiety (rlipo-E7m) has been demonstrated to induce robust CTL responses against small tumors. This treatment in combination with other TLR agonists is able to eliminate large tumors.MethodsMouse bone marrow-derived dendritic cells (DCs) were employed to determine the synergistic production of pro-inflammatory cytokines upon combination of rlipo-E7m and other TLR agonists. Antigen-specific CTL responses were investigated using immunospots or in vivo cytolytic assays after immunization in mice. Mice bearing various tumor sizes were used to evaluate the anti-tumor effects of the formulation. Specific subpopulations of immunosuppressive cells in the tumor infiltrate were quantitatively determined by flow cytometry.ResultsWe demonstrate that a TLR9 agonist (unmethylated CpG oligodeoxynucleotide, CpG ODN) enhances CTL responses and eradicates large tumors when combined with rlipo-E7m. Moreover, combined treatment with rlipo-E7m and CpG ODN effectively increases tumor infiltration by CTLs and reduces the numbers of myeloid-derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs) and regulatory T cells (Tregs) in the tumor microenvironment.ConclusionThese findings suggest that the dramatic anti-tumor effects of the recombinant lipoprotein together with CpG ODN may reflect the amplification of CTL responses and the repression of the immunosuppressive environment. This promising approach could be applied for the development of additional therapeutic cancer vaccines.

【 授权许可】

Unknown   
© Chang et al.; licensee BioMed Central Ltd. 2014. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.