In small animal models, the application of surgical stress can be shown to reproducibly increase the success rate of tumor implantation, the rate of growth and the size of primary tumor, and the rate, size, and incidence of subsequent metastases. Surgical stress-induced metastases may be related to impaired blood stream clearance and increased pulmonary localization of circulating tumor emboli, as has been noted in the rat as early as 1 hr. after surgery. Among the many host responses that are important in the control of circulating tumor emboli, the natural killer cell may be particularly critical because of its emerging role as a first line of defense against the intravascular route of metastasis. Because tumor emboli are generated in humans undergoing tumor resection, and because murine and human studies conducted by ourselves and others demonstrate a profound and acute impairment of perioperative NK cytotoxicity, we would like to elucidate the underlying mechanism of this NK cell impairment and develop in vitro preclinical therapy for this impairment process. Specifically, this project will determine the mechanism of human perioperative NK cell cytotoxicity impairment by detecting the presence and possible identity of surgically generated NK-suppressing cells. The possible surgically-mediated NK cell depletion or direct toxic down regulation of NK cells will be examined. Defects in NK cell tumor binding, tumor lysis, and cellular recycling will be determined. The role of NK cells in lysis of autologous tumor perioperatively will be determined. Finally, preclinical therapy in vitro using biologic response modifiers to stimulate NK cell antitumor cytolysis will be developed. It is hoped that fulfilling these specific aims will ultimately lead to NK-specific perioperative immunotherapy trials in the future.
| Gutman, H; Risin, D; Pollock, R E et al. (1993) Effect of surgery on peripheral blood lymphocyte locomotion through type I collagen. Cancer 71:2833-7 |
| Pollock, R E; Lotzova, E; Stanford, S D (1992) Surgical stress impairs natural killer cell programming of tumor for lysis in patients with sarcomas and other solid tumors. Cancer 70:2192-202 |
| Pollock, R E; Lotzova, E; Stanford, S D (1991) Mechanism of surgical stress impairment of human perioperative natural killer cell cytotoxicity. Arch Surg 126:338-42 |
| Pollock, R E; Zimmerman, S O; Fuchshuber, P et al. (1990) Lytic units reconsidered: pitfalls in calculation and usage. J Clin Lab Anal 4:274-82 |
