Abstract LB-136: Targeting perivascular macrophages to prevent castration resistance in men with high-risk, localized prostate cancer

Abstract

Abstract Background: Men with intermediate/high-risk, localised prostate cancer are usually offered androgen deprivation therapy (ADT) and if this fails, radical prostatectomy. Men understandably prefer not to have the latter where possible as it often leads to unpleasant side effects like urinary incontinence and erectile dysfunction. So, maximising the efficacy of ADT and/or preventing subsequent castration resistance is of clinical importance. A distinct subset of macrophages in tumours - those that make intimate contact with the abluminal side of tumour blood vessels and express high levels of MRC1, TIE2, CXCR4 and VEGFA - have been shown to play a crucial role in tumour relapse after chemotherapy by stimulating tumour angiogenesis and regrowth, as well as the escape of metastasizing cancer cells into the circulation, and suppression of tumour-infiltrating T cells. These perivascular (PV) cells have also been shown to stimulate tumour regrowth after irradiation and treatment with vascular targeting drugs. In this project, we investigated the effects of castration (which mimics the effects of ADTs) on PV macrophages in a syngeneic, orthotopic model of localised prostate cancer. Methods: Mice bearing established, LUC-expressing Myc-CaP tumours were either castrated or sham-castrated at day 10 post-inoculation and tumour growth assessed using the IVIS Imaging system. Multicolour immunofluorescent analysis of tumour sections (for CD31, MRC1, F4/80 and DAPI) was then performed on sections of excised tumours to assess the accumulation of PV macrophage just before, and immediately after, the regrowth of tumours. Results: Castration caused a marked delay in tumour growth in this mouse model with castration resistance evident within 2 weeks when tumours started to grow vigorously. Both the number and proportion of MRC1+ macrophages making direct contact with the abluminal surface of CD31+ blood vessels increased markedly just prior to castration resistance, and was persisted in tumours that had regrown to the size of sham-castrated ones at the end of the experiment. Conclusion: Our data indicate that PV MRC1+ macrophages may play a role in the development of castration resistance and/or subsequent tumour regrowth in mouse Myc-CaP tumours. We are currently investigating this using MRC1-targeting liposomes to inhibit the tumour-promoting functions of PV TAMs in mouse prostate tumours. We are also examining the accumulation and function of PV macrophages in AADT-responsive versus castration resistant localised human prostate tumours. It is hoped that these studies will lead to the use of macrophage-targeting liposomes to enhance the efficacy of ADTs in men with localised prostate cancer. Citation Format: Xuan Pu, Haider AL-Janabi, Ning Wang, Munitta Muthana, Janet Brown, Claire Lewis. Targeting perivascular macrophages to prevent castration resistance in men with high-risk, localized prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-136.