Abstract 4571: Pro-inflammatory and pro-angiogenic properties of tumor associated natural killer cells in prostate cancer

Abstract

Abstract Prostate cancer (PCa) represents the second cause of male cancer death worldwide. Immune cells can acquire pro-tumor phenotype and functions as consequence of their plasticity. Natural killer (NK) cells are cellular mediators of the innate immunity, primarily involved in tumor recognition and elimination. Altered NK phenotype and functions have been observed in different tumors including PCa. Here, we provide new insights on phenotype and functional characterization of peripheral blood tumor-associated NK cells (TANKs) from benign prostatic hyperplasia (BPH) and prostatic adenocarcinoma (ADK) patients. We also investigated NK interaction with other components of the tumor microenvironment. NK cell phenotype and functional characterization was performed by multicolour flow cytometry for surface antigens on BPH and PCa TANKs. Interactions of TANKs with other TME components (endothelial cells, macrophages) were investigated using released products from BPH and PCa TANKs for functional studies of angiogenesis, macrophage recruitments and polarization. The effects of TANKS on macrophage polarization state were evaluated by gene expression analysis RT-PCR (qPCR).We found that NK cells from peripheral blood of BPH and PCa patients acquire a pro-angiogenic/ decidual-like phenotype, identified as CD56+CD9+CD49a+CD69+ NKs. These results were confirmed also exposing heathy-donor derived NKs to conditioned media of 3 different prostate cancer cell lines (PC-3, DU-145, LNCaP). In addition, polarization of NKs with the PCa cell line conditioned media resulted in downregulation of IFNγ, TNFα and Granzyme A and increased production of pro-angiogenic factors, such CXCL8, Angiopoietin1 (Angiop1) and Angiogenin (ANG). Secretome analysis revealed the ability of NKs from BPH and PCa patients to release higher level of pro-angiogenic molecules (CXCL8, MMP-1, MMP-9 and uPAR) and cytokines/chemokines involved in macrophage recruitment, CCL1, CCL2, CCL5, CCL13, CXCL1, CXCL11 and GM-CSF. Conditioned media from BPH and PCa NKs were able to promote angiogenesis in vitro, by inducing the formation of capillary-like structures on human umbilical-vein endothelial cells (HUVEC), recruit the THP-1 monocyte cell line and polarize THP-1 differentiated macrophage towards M2-like tumor associated macrophages (TAM).Our data demonstrate that NK cells from PCa patients are switched toward a pro-angiogenic/pro-tumor phenotype and function. Therefore, we propose tumor associated NKs as a new hallmark and potential target in prostate cancer. Citation Format: Denisa Baci, Matteo Gallazzi, Lorenzo Mortara, Douglas M. Noonan, Antonino Bruno. Pro-inflammatory and pro-angiogenic properties of tumor associated natural killer cells in 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 4571.