Natural killer (NK) cells are an important defense against intravascular tumor dissemination. Tumor embolization can occur at surgery, so we tested whether surgical stress decreased perioperative NK cell cytotoxicity, and examined the underlying mechanism of suppression. Patients with solid tumors underwent NK cell cytotoxicity assay just before and 24 hours after surgery in a 3-hour chromium 51 release assay. The NK cell cytotoxicity was significantly decreased postoperatively. We considered that surgical NK cell impairment might be due to (1) NK cell redistribution, (2) presence of suppressor cells, or (3) direct "toxic" effects on NK cells. Impaired NK cell cytotoxicity was not due to NK cell redistribution, because differential counts showed no significant changes in the percentage of large granular lymphocyte NK morphology. To isolate possible suppressor cells, postoperative cells from patients were selectively depleted of NK cells using anti-Leu-11b monoclonal antibody plus complement; these cells were then mixed with autologous preoperative cells. Postoperative NK cell cytotoxicity was markedly impaired, but the postoperative NK depleted cells did not suppress preoperative NK cells. We conclude that NK cell functional impairment from surgical stress is due to direct "toxic" effects on NK cells rather than either NK cell redistribution or the generation of NK-directed suppressor cells.

Background. Natural killer (NK) cells may provide a first line of defense against the metastatic implantation of circulating tumor emboli. Because tumor emboli are discharged systemically in patients undergoing solid tumor resection, it is important to determine the nature of surgical‐stress impairment of perioperative NK cell cytotoxic function. Methods. The authors studied 85 patients undergoing surgical resection of solid tumors, most of whom had an abrupt and marked decrease in NK cell cytotoxicity that was detectable within 18 hours of surgical resection. Results. This impairment was not caused by rapidly emerging suppressor cells (measured in autologous effector cell mixing studies) or decreased NK cell frequency in the peripheral blood (assessed phenotypically and morphologically). Instead, surgical stress exerted a direct “toxic” effect on NK cells that could be localized to a specific phase of the NK cell tumor lysis cycle. Tumor binding and the first round of tumor lysis were intact postoperatively (measured in single‐cell assays). However, postbinding programming for lysis was decreased sharply after surgery (assessed by calcium pulse assays). In addition, the kinetics of lysis and the rate of lytic programming were slower after surgery (assayed in target saturation kinetic chromium‐51 release tests). Conclusions. These latter defects probably were related to the programming for lysis deficiency because postprogramming NK cell maximal recycling capacity was not affected by surgical stress.

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51Chromium release-derived cytotoxicity data yield curvilinear plots when the x axis displays the effector:target ratio and the y axis displays the percentage of cytotoxicity. To facilitate data analysis, several biomathematical models (simple linear regression, exponential fit, and Von Krogh) have been used to express these cytotoxicity curves as a single numerical value, termed the lytic unit. Other than using raw cytotoxicity data, the lytic unit has been the most common method of data presentation in human and animal tumor immune studies involving natural killer cells, lymphokine-activated killer cells, and cytotoxic T cells. Unfortunately, the models for determining lytic unit values incorporate assumptions and methods of calculation that can result in inaccurate model-predicted cytotoxicity in comparison with the actual observed cytotoxicity data. Even when the model is accurate in predicting cytotoxicity values (i.e., the nonlinear regression-calculated three-parameter Von Krogh model), comparisons between donors of minimally different or highly different cytotoxicity are still fraught with potential error due to statistically verifiable violations of assumptions of parallelism. Although more cumbersome, donor cytotoxicity comparisons using a range of effector:target ratios are not subject to the above problems. Researchers may therefore want to reconsider the use of lytic units when evaluating and reporting cytotoxicity data.