Preventing Postoperative Metastatic Disease by Inhibiting Surgery-Induced Dysfunction in Natural Killer Cells

Lee-Hwa Tai,Tiffany Lam,Andrew P Makrigiannis,Julia L Rintoul,Jiqing Zhang,Christiano Tanese De Souza,Rebecca A Auer,Lundi Ly,Abhirami A Ananth,David H Kirn,Theresa J Falls,John C Bell,Simon Bélanger,Almohanad A Alkayyal,Caroline J Breitbach

doi:10.1158/0008-5472.can-12-1993

Abstract

Natural killer (NK) cell clearance of tumor cell emboli following surgery is thought to be vital in preventing postoperative metastases. Using a mouse model of surgical stress, we transferred surgically stressed NK cells into NK-deficient mice and observed enhanced lung metastases in tumor-bearing mice as compared with mice that received untreated NK cells. These results establish that NK cells play a crucial role in mediating tumor clearance following surgery. Surgery markedly reduced NK cell total numbers in the spleen and affected NK cell migration. Ex vivo and in vivo tumor cell killing by NK cells were significantly reduced in surgically stressed mice. Furthermore, secreted tissue signals and myeloid-derived suppressor cell populations were altered in surgically stressed mice. Significantly, perioperative administration of oncolytic parapoxvirus ovis (ORFV) and vaccinia virus can reverse NK cell suppression, which correlates with a reduction in the postoperative formation of metastases. In human studies, postoperative cancer surgery patients had reduced NK cell cytotoxicity, and we show for the first time that oncolytic vaccinia virus markedly increases NK cell activity in patients with cancer. These data provide direct in vivo evidence that surgical stress impairs global NK cell function. Perioperative therapies aimed at enhancing NK cell function will reduce metastatic recurrence and improve survival in surgical cancer patients.

Highlights

Surgeons have long suspected that surgery, a necessary step in the treatment of solid cancers, facilitates the metastatic process
We have developed a reproducible mouse model of surgical stress that results in the dramatic enhancement of pulmonary metastases
The underlying mechanism of surgical stress resulting in increased metastases seems to involve Natural killer (NK) cells

Summary

Introduction

Surgeons have long suspected that surgery, a necessary step in the treatment of solid cancers, facilitates the metastatic process. Numerous animal studies using implanted and spontaneous tumor models have clearly shown that surgery promotes the formation of metastatic disease [2, 3], and the number of metastatic deposits that develop is directly proportional to the magnitude of surgical stress [2]. A complicated postoperative course corrresponds to an increase in physiologic surgical stress. This has been shown to correlate with an inferior cancer survival and an increased incidence of metastatic disease [4, 5]. A number of perioperative changes have been proposed to explain the promotion of metastases formation following

Methods

Results

Conclusion