Immunotherapy for prostate cancer has recently emerged as an attractive treatment strategy. Yet, preclinical models where relationship between inflammation, stroma, tumor cells and prostate cancer progression can be studied are limited. GEMM models of prostate cancer are scarce and in xenograft models, even when in humanized mice, the role of immune system in the initiation and in progress of the malignancy cannot be studied. As the requirement to test novel immunotherapies and especially combination treatments is increasing, a preclinical model that takes into account tumor microenvironment and immune system would be highly useful to promote development of novel therapies to combat against prostate cancer. Aim of the present study was to reveal if there is role between the immune system and development of prostate cancer, and secondly, to validate a model to be utilized later in immunotherapy development.
Intact 10-12 weeks old male Noble rats were s.c. implanted with slow-releasing estradiol and testosterone pellets for 6, 13 and 18 weeks. Daily release for testosterone was 0.8 mg and for estradiol 0.08 mg. Control group animals received placebo hormone pellets without hormones. Serum samples were collected during the study to monitor hormone levels, and prostates were removed and processed for histopathological evaluation at the end of the study. Hormonal treatment caused an increase in estradiol to testosterone ratio, and the prostates were enlarged. Imbalance in hormone-milieu induced inflammation in the prostate, followed by formation of prostatic intraepithelial neoplasia (PIN)-like lesions and finally adenocarcinomas in the periurethral region. Inflammatory cells, mainly T-cells were noticed in the vicinity of PIN-like lesions. During the progression of prostate cancer, inflammatory cells disappeared from the adenocarcinoma sites. In the prostate, inflammation consisting of perivascular, stromal and periglandular T-lymphocytes and intraluminal neutrophils remained.
Results of this study indicate significance of hormonal milieu, especially estrogens and androgens, in the development of inflammation and progression of prostate cancer, with a key role for tumor microenvironment. Presence of lymphocytes in the proximity of PIN-like lesions during the early phases of prostate cancer, and their disappearance later in the adenocarcinomas, indicate interaction between innate and adaptive immune system and cancer. Therefore, this preclinical prostate cancer model that combines immune system and cancer can be utilized when new immunotherapies, combination treatments and prevention possibilities against prostate cancer progression are developed.
Citation Format: Mari I. Suominen, Tiina Kähkönen, Yvonne Konkol, Jenni Mäki-Jouppila, Jussi M. Halleen, Jenni Bernoulli. Preclinical efficacy model to promote immunotherapy development for prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1663. doi:10.1158/1538-7445.AM2017-1663