Depression of nonadaptive immunity after surgical stress: influence on metastatic spread.

The question of increased tumor cell dissemination after surgical stress was addressed in the model system of the spontaneously metastasizing rat adenocarcinoma BSp73ASML, wherein amputation of the hind leg 7 days after intrafootpad implantation of tumor cells cured the animals, while surgical stress by laparotomy 2 days prior to amputation resulted in lung metastases in 80% of rats. A detailed in vitro analysis of natural killer (NK) and macrophage (Mo) activity in different lymphatic compartments revealed the following impacts of surgery: splenic NK cells displayed unaltered activity. Yet, there was a considerable decrease in the number of lymphoid cells during the first 4 days after surgery, being followed by an overshooting repopulation. In the peripheral blood, activity levels of NK cells dropped significantly during the first 24 h after surgery; later on, NK cells appeared activated with an over 2-fold increase in lytic units (LU), 4 days after surgery, NK activity had returned towards normal levels. Most dramatic changes were observed in the peritoneal cavity, being directly involved in the surgical intervention. Six hours after surgery the peritoneal cavity was nearly depleted of NK cells and Mo, the few remaining cells being highly activated. Within 2 days the peritoneal cavity was repopulated with a 3-4 fold excess of lymphoid cells and Mo, but the repopulating cells were extremely low in lytic activity. It is concluded that depression of nonadaptive immunity after surgical stress is mainly due to traffic and repopulation with immature cells, i.e. there was no indication of suppressor cell activity. This was confirmed by a combined treatment consisting in a systemic application of Corynebacterium parvum 2 days before surgery and a local application of C. parvum after surgery, which counter-balanced the stress-induced depression of NK and Mo activity. Accelerated and increased metastatic spread could be prevented concomitantly.