Treatment combining RU486 and Ad5IL-12 vector attenuates the growth of experimentally formed prostate tumors and induces changes in the sentinel lymph nodes of mice

Journal of Translational Medicine

Research

Frank L Graham¹  Jack Gauldie¹  Todd A Braciak²  Eli E Sercarz²  Jennifer Gee²  Claudia Raja Gabaglia²  Alexandra DeLaney²  Ramesh Halder³ 

[1] Department of Pathology and Molecular Medicine, McMaster University, 1200 Main Street West, L8N 3Z5, Hamilton, ONT, Canada;Division of Immune Regulation, Torrey Pines Institute for Molecular Studies (TPIMS), 3550 General Atomics Court, 92121, San Diego, CA, USA;Laboratory of Autoimmunity, Torrey Pines Institute for Molecular Studies (TPIMS), 3550 General Atomics Court, 92121, San Diego, CA, USA;

关键词: Prostate Cancer;    Mifepristone;    Tumor Immunity;    Mitotane;    Human Prostate Cancer Cell Line;   

DOI  :  10.1186/1479-5876-8-98

 received in 2010-06-15, accepted in 2010-10-14,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundTumor immune responses are first generated and metastases often begin in tumor sentinel lymph nodes (TSLN). Therefore, it is important to promote tumor immunity within this microenvironment. Mifepristone (RU486) treatment can interfere with cortisol signaling that can lead to suppression of tumor immunity. Here, we assessed whether treatment with RU486 in conjunction with an intratumor injection of Ad5IL-12 vector (a recombinant adenovirus expressing IL-12) could impact the TSLN microenvironment and prostate cancer progression.MethodsThe human PC3, LNCaP or murine TRAMP-C1 prostate cancer cell lines were used to generate subcutaneous tumors in NOD.scid and C57BL/6 mice, respectively. Adjuvant effects of RU486 were looked for in combination therapy with intratumor injections (IT) of Ad5IL-12 vector in comparison to PBS, DL70-3 vector, DL70-3 + RU486, RU486 and Ad5IL-12 vector treatment controls. Changes in tumor growth, cell cytotoxic activity and populations of CD4+/FoxP3+ T regulatory cells (Treg) in the TSLN were evaluated.ResultsTreatment of human PC3 prostate xenograft or TRAMP-C1 tumors with combination Ad5IL-12 vector and RU486 produced significantly better therapeutic efficacy in comparison to controls. In addition, we found that combination therapy increased the capacity of TSLN lymphocytes to produce Granzyme B in response to tumor cell targets. Finally, combination therapy tended towards decreases of CD4+/FoxP3+ T regulatory cell populations to be found in the TSLN.ConclusionInclusion of RU486 may serve as a useful adjuvant when combined with proinflammatory tumor killing agents by enhancement of the immune response and alteration of the TSLN microenvironment.

【 授权许可】

Unknown   
© Gabaglia et al; licensee BioMed Central Ltd. 2010. 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 cited.