Abstract 1080: The adaptive immune system promotes spontaneous prostate carcinogenesis in a transgenic mouse model
Authors: Melis Monique H.M , Burgsteden J. van , Zeeburg H J.T van , Zevenhoven J , Song J-Y , Visser K E. de , Bergman A M. 
Published: May 2015

Abstract
Increasing evidence from epidemiological and pathological studies indicates a role of the immune system in initiation and progression of multiple cancers, including prostate cancer. Throughout carcinogenesis of the prostate, immune cells are found in the microenvironment. Overexpression of MYC or loss of PTEN are frequent genetic lesions in human prostate cancer. It has been shown that these genetic lesions induce chemokine expression and attraction of immune cells. In previous studies the adaptive system has shown to play a pivotal role in disease progression, however the role of the adaptive immune system in prostate carcinogenesis has been inadequately studied.
In this study we address the role of the adaptive immune system in the development of prostate cancer in two independent spontaneous prostate cancer mouse models; the FVB/HiMYC mouse model in which prostate cancer formation is driven by transgenic expression of human MYC under control of the ARR2/probasin promoter, and the PB-Cre;PTENF/F mouse model in which prostate cancer formation is initiated by loss of PTEN expression. Both mouse models develop Prostatic Intraepithelial Neoplasia (PIN) from the age of 4 weeks on. FVB/HiMYC mice develop adenocarcinoma of the prostate from the age of 24 weeks and PB-Cre;PTENF/F mice from the age of 12 weeks on. To address the functional significance of lymphocytes in prostate cancer development, FVB/HiMYC and PB-Cre;PTENF/F were crossed to lymphocyte deficient RAG-1-/- mice. Analysis of the PTEN model is ongoing, however in the HiMYC model a small but significant delay (p&lt;0.05) in latency of invasive carcinoma development was found in RAG-1-/- compared to RAG-1+/- mice suggesting a promoting role of the adaptive immune system in prostate cancer initiation and/or progression.
Marked inflammation and increased nuclear BrdU incorporation was found in concert with prostate cancer development. Flow cytometry confirmed an increase in CD45 positive cells in the prostate already in pre-cancerous lesions, which was not observed in the peripheral blood. A significant increase in CD45+ cells in HiMYCRAG-1+/- was found compared to HiMYCRAG-1-/- at 24 weeks, with the majority being CD11b positive cells. This finding was strengthen by increased expression of cytokines involved in the chemo-attraction of macrophages and neutrophils, including CXCL1, CXCL2, CXCL5 and CCL5 which was observed in HiMYCRAG-1+/- mice compared to HiMYCRAG-1-/-
In conclusion: Our study provides insight into the role of the adaptive immune system in prostate cancer development. In the absence of T and B cells, the composition of infiltrating immune cells and cytokine expression in the microenvironment is altered, which might contribute to the delay of prostate cancer development.
This research was funded by a grant from the Dutch Cancer Society (KWF grant 2009-4356)
Citation Format: Monique H.M Melis, J. van Burgsteden, H J.T van Zeeburg, J Zevenhoven, J-Y Song, K E. de Visser, A M. Bergman. The adaptive immune system promotes spontaneous prostate carcinogenesis in a transgenic mouse model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1080. doi:10.1158/1538-7445.AM2014-1080