Abstract 528: Preventing perioperative cancer metastases formation by enhancing Natural Killer cell activity

Abstract

Abstract Background: Surgical resection is the mainstay of therapy for patients with localized solid malignancies. Even with complete resection, many patients develop metastatic recurrence and ultimately die of their disease. The perioperative period is a uniquely susceptible time for the formation of metastases. A number of changes that occur following surgery promote the formation of metastases, including dissemination of tumour cells, a pro-mitotic and pro-angiogenic milieu and suppression of the immune system. Natural Killer (NK) cells are a key component of the innate immune response against cancer, in particular the elimination of micrometastases. NK cell suppression and dysfunction have been linked to the development of metastatic disease in animal models and in cancer patients. Objective: We hypothesized that surgical stress enhances the development of postoperative metastases by impairing NK clearance of tumor cells. Specifically, we aim to 1) define the mechanisms involved in NK cell suppression following surgery and 2) explore novel anti-cancer therapies to modulate postoperative NK cell suppression and inhibit metastases. Methods: A mouse model of surgical stress and tumor metastases was used to address these questions. In this model, NK cell functions were assessed using immunological functional assays following tumor challenge, surgical stress and novel perioperative anti-cancer therapy. Results and Conclusions: We observed enhanced lung metastases in tumor-bearing NK-deficient mice that received adoptively transferred NK cells from surgically stressed mice compared to NK cells from untreated mice. This establishes that NK cells play a crucial role in mediating the prometastatic effect of surgery. Accordingly, in vivo CFSE labeled MHC-I-deficient splenocyte and RMA-S tumor cell rejection and ex vivo chromium labeled YAC-1 and B16 tumor target cell killing by NK cells were significantly reduced in surgically stressed mice compared to untreated mice. A significant reduction in spleen NK cell surface expression of NKG2D and KLRG1 receptors were also observed in surgically stressed mice. These data suggest that surgical stress impairs global NK cell function. For the therapeutic arm of our project, we have demonstrated that using the perioperative administration of the non-specific NK cell activator poly I:C can reverse NK cell suppression following surgery and that this correlates with a reduction in the postoperative formation of metastases. We have also evaluated oncolytic vaccinia virus and observed a similar attenuation of metastases and recovery of NK cytotoxicity following perioperative administration. Significance of Research: Cancer therapies aimed at targeting the mechanisms responsible for the prometastatic effects of surgery will reduce recurrences and improve survival in surgical cancer patients when used in the perioperative period. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 528. doi:1538-7445.AM2012-528