Abstract
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.
Highlights
Tumor immune responses are first generated and metastases often begin in tumor sentinel lymph nodes (TSLN)
RU486 augments antitumor activity of Ad5IL-12 in PC3 xenograft model Given that RU486 inhibits androgen signaling, we began our studies on androgen-independent human prostate cancer cell line PC-3 tumors formed subcutanously in NOD.scid mice
Combination therapy resulted in mice with average tumor volumes of 298 ± 120 mm3 at the 8 week time point, representing an additional 2.24-fold reduction in tumor mass when compared to the Ad5IL-12 vector treatment alone (p = 0.029) and a 6.70-fold difference against the RU486 treatment alone (p = 0.010)
Summary
Tumor immune responses are first generated and metastases often begin in tumor sentinel lymph nodes (TSLN). 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. Prostate cancer is one of the leading causes of death in men and has not been curable once it has metastasized beyond the local prostate gland [1] This poor effect of current therapy on metastases could be the result of immunosuppressive conditions found in tissue microenvironments where metastatic cancer cells migrate including the TSLN. We have previously used a recombinant adenovirus vector expressing the IL-12 cytokine (Ad5IL-12) in combination with mitotane, a drug that transiently suppresses cortisol production, to enhance the activity of the vector and produce more successful therapy of experimental prostate cancers in mice [8]. Given that RU486 is an approved pharmaceutical and affect pathways of homeostatic regulation, we sought to evaluate whether it would be useful as an immunological adjuvant in cancer therapy
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