Abstract 3147: Adipocytes affect castration-resistant prostate cancer cells in resistance to cytotoxic action of NK cells through alterations of pd-l1/nkg2d ligand levels
Authors: Xu Lijun , Shen Mingjing , Chen Xiaodong , Zhu Rongying , Yang Dong-rong , Tsai Ying , Keng Peter , Chen Yuhchyau , Lee Soo Ok 
Published: August 2018

Background: One-third of US population is obese. The mortality of obese prostate cancer (PCa) patients is higher than non-obese patients, thus studying molecular mechanism of how obesity affects PCa progression has clinical relevance. The periprostatic adipose tissue adjacent to the prostate is considered a driving force of disease progression and adipocytes are the main cell population in adipose tissues. The paracrine role of adipocytes in PCa progression has been emphasized, but its implication in modulating immune reactions remains unknown. We investigated the role of adipocytes in the surveillance of castration-resistant PCa (CRPC) cells to immune actions. Especially we investigated the role of adipocytes in affecting tumor cell susceptibility to cytotoxic action of natural killer (NK) cells, as the strategy of improving the NK cell-mediated immunity is emerging as an immunotherapeutic option.

Methods: Using primary NK cells as the NK cell source, NK cell cytotoxicities to CRPC cells, either control media treated or adipocyte-conditioned media (CM) treated, were tested in lactate dehydrogenase (LDH) release-based assays. The levels of programmed death receptor ligand (PD-L1) and NK group 2D (NKG2D) ligands in adipocyte CM-treated CRPC cells were analyzed in qPCR analyses. Effects of blocking adipocyte action on altering PD-L1/NKG2D ligand levels and the susceptibility of CRPC cells to NK cell cytotoxicity were investigated.

Results: We found NK cell cytotoxicity to CRPC cells decreased when tumor cells were treated with adipocyte CM, and was associated with PD-L1 (up-regulation) and NKG2D ligand level (down-regulation) alterations. Further, we discovered that the JAK/Stat3 signaling pathway was activated by adipocyte CM. Two adipokine molecules, IL-6 and leptin, were shown to be important in the activation of the JAK/Stat3 signaling to modulate the PD-L1/NKG2D ligand level alterations in CRPC cells. Consequently, adding inhibitors of JAK/Stat3 signaling or neutralizing antibodies of IL-6 or leptin increased the susceptibility of CRPC cells to NK cell cytotoxic action.

Conclusions and Impact: Results from our study showed the influence of adipocytes on tumor cells and resulted in reducing the susceptibility to NK cell-mediated antitumor immune function. This may be one of ways that adipocytes trigger CRPC cells to be more aggressive and out of immune surveillance control. Our study results showed that blocking the adipocyte effect by inhibiting the IL-6/leptin-JAK/Stat3 signaling axis enhanced the NK cell mediated immunity to CRPC cells. We suggest that this strategy can be applied to the development of future immune therapeutics to treat obese PCa patients.

Citation Format: Lijun Xu, Mingjing Shen, Xiaodong Chen, Rongying Zhu, Dong-rong Yang, Ying Tsai, Peter Keng, Yuhchyau Chen, Soo Ok Lee. Adipocytes affect castration-resistant prostate cancer cells in resistance to cytotoxic action of NK cells through alterations of pd-l1/nkg2d ligand levels [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3147.