Abstract 2797: Changes in the phenotype of macrophages and CD8+ T Cells in the perivascular niche of prostate tumours following androgen deprivation
Authors: Haider Al-janabi, Xuan Pu, Munitta Muthana, Ning Wang, Mateus Crespo, Bora Gurel, Johann De Bono, Janet E. Brown, Claire E. Lewis
Journal: Cancer Research (2021)

Abstract Men with intermediate/high-risk, localized prostate cancer usually receive neoadjuvant androgen deprivation therapy (ADT). Although this markedly reduces tumor burden, it may not be curative and over time cancer cells develop resistance to ADT causing the tumor to regrow and spreads to other sites like the bones. Tumors are then termed ‘castration resistant' (CR) and require more aggressive forms of treatment like radical prostatectomy (RP) and chemotherapy. These can have unpleasant side effects so preventing the development of castration resistance and subsequent tumor regrowth/metastasis, would be highly beneficial for patients. A distinct subset of perivascular (PV) tumor-associated macrophages (TAMs) expressing the cell-surface receptor, MRC1, has been shown to be proangiogenic, immunosuppressive and to stimulate tumor regrowth after chemotherapy, irradiation or vascular targeting drugs. In the current study, we have examined the density and phenotype of TAMs in PV vs non-PV areas of localized, human prostate tumors and orthotopic mouse (Myc-CaP) tumors following neoadjuvant ADT or castration respectively. In human tumors, MRC1+ TAMs accumulated at highest density around stromal blood vessels, and were abundant in these sites following ADT. In mice, castration markedly reduced primary tumor growth and changed the distribution and phenotype of TAMs and cytotoxic CD8+ T lymphocytes (CTLs) just prior to the development of CR. In PV areas of tumors in sham-castrated (i.e. control) mice there were significantly more TAMs expressing MRC1 and the broad-spectrum negative checkpoint regulator, VISTA than in non-PV areas. This was accompanied by the preferential accumulation of CTLs around blood vessels (contrasting with the even distribution of CD4+ (helper) cells and CD4+FOXP3+ Tregs across PV and non-PV areas). Following castration, the PV density of MRC1+ and VISTA+ TAMs was markedly increased, along with that of CTLs expressing the cytotoxic protease, granzyme B - a marker of active CTLs. Although these cells may cross the vasculature into tumors in an active state, passing through a PV niche enriched in VISTA+ TAMs would likely suppress their cytotoxic function before they progressed into the tumor mass. An interesting picture is, therefore, emerging of tumor-promoting TAMs accumulating around blood vessels after various forms of treatment, where they regulate a number of important events including the extravasation and function of various immune effectors. Citation Format: Haider Al-janabi, Xuan Pu, Munitta Muthana, Ning Wang, Mateus Crespo, Bora Gurel, Johann De Bono, Janet E. Brown, Claire E. Lewis. Changes in the phenotype of macrophages and CD8+ T Cells in the perivascular niche of prostate tumours following androgen deprivation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2797.