Abstract A135: Phosphodiesterase-5 inhibition augments postoperative natural killer cell antitumor immunity by reducing myeloid-derived suppressor cell function (2016)

Abstract Background and Objective: Cancer surgery while necessary for primary tumor removal, has been shown to induce immune suppression and promote metastases in preclinical models and human cancer surgery patients. We have previously shown that cancer surgery induces natural killer (NK) cell dysfunction and promotes postoperative metastases formation. Activating the immune system and reversing immune suppression have emerged as promising ways to treat cancer and they can be safely employed in the perioperative period. In this study, we investigated the role of Myeloid-Derived Suppressor Cells (MDSC) as the mediators of postoperative NK cell impairment and subsequent metastases and evaluated the ability to target MDSC with a phosphodiesterase-5 (PDE-5) inhibitor in the clinically relevant postoperative period. Methods: The suppression of NK cell cytotoxic activity by MDSC from control and surgically stressed mice was compared both in vitro and in vivo. Further, NK cell function and lung tumor burden was assessed following perioperative PDE-5 administration. In human cancer patients, MDSC expansion and function were assessed prior to and following surgical resection. Results: MDSC expansion was observed following surgery in mouse melanoma and breast tumor models of surgical stress and this correlates with NK cell suppression postoperatively. Co-cultures of NK cells with MDSC from control and surgical stressed mice resulted in their functional suppression with surgically stressed MDSC, but not with control MDSC. Adoptive tranfser of MDSC from surgically stressed donor mice into recipient mice resulted in impaired in vivo clearance of NK cell sensitive RMA-S tumor cells. Further, surgically stressed mice depleted of MDSC, demonstrated enhanced ability to clear RMA-S tumor cells and fewer lung tumour metastases. Using the clinically relevant PDE-5 inhibitor (sildenafil) to target MDSC suppressive pathways, we demonstrated recovery of NK cell in vitro and in vivo function, followed by reduction of lung tumor metastases. In human cancer surgery patients, MDSC expansion and suppression of NK cells in co-culture with autologous MDSC was observed in the early postoperative period. Conclusions and Significance: MDSC are increased in both number and suppressive activity of NK cells following surgery. MDSC represent a hurdle to successful treatment of postoperative metastatic disease, but this effect is reversible using PDE-5 inhibitors. A clinical trial of perioperative PDE-5 inhibitors is currently being undertaken. Citation Format: Lee-Hwa Tai, Almohanad A. Alkayyal, Christiano Tanese de Souza, Amanda Lynn Leslie, Shalini Sahi, Sean Bennett, Jiqing Zhang, John C. Bell, Rebecca A. Auer. Phosphodiesterase-5 inhibition augments postoperative natural killer cell antitumor immunity by reducing myeloid-derived suppressor cell function. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A135.