Intraperitoneal oxidative stress in rabbits with papillomavirus-associated head and neck cancer induces tumoricidal immune response that is adoptively transferable.

PURPOSE: How tumors evade or suppress immune surveillance is a key question in cancer research, and overcoming immune escape is a major goal for lengthening remission after cancer treatment. Here, we used the papillomavirus-associated rabbit auricular VX2 carcinoma, a model for studying human head and neck cancer, to reveal the mechanisms underlying the antitumorigenic effects of intraperitoneal oxidative stress following O3/O2-pneumoperitoneum (O3/O2-PP) treatment. EXPERIMENTAL DESIGN: Solid auricular VX2 tumors were induced in immune-competent adult New Zealand White Rabbits. Animals were O3/O2-PP- or sham-treated, after which they underwent tumor ablation upon reaching no-go criteria. CD3(+) tumor-infiltrating lymphocytes (TIL) were evaluated by immunohistochemistry, and expression levels of 84 immune response genes were measured by quantitative real-time PCR. Adoptive transfer of peripheral blood leukocytes (PBL)-derived from animals with tumor regression-into control animals with progressing tumors was implemented to assess acquired tumor resistance functionally. RESULTS: Auricular VX2 tumors regressing after O3/O2-PP treatment exhibited increased levels of CD3(+) TILs; they also exhibited enhanced expression of genes that encode receptors involved in pattern recognition, molecules that are required for antigen presentation and T cell activation, and inflammatory mediators. Adoptive cell transfer of PBLs from donor rabbits with regressing tumors to recipient rabbits with newly implanted VX2 carcinoma resulted in acquired tumor resistance of the host and tumor regression. CONCLUSION: Intraperitoneal oxidative stress effectively converts the immune response against the papillomavirus-associated rabbit VX2 carcinoma from tumor permissive to tumoricidal and leads to a sustainable, adoptively transferable oncolytic immune response.

The effect of the pneumoperitoneum on the peritoneal defense mechanisms in diabetic rats.

To investigate the effects of pneumoperitoneum on the peritoneal defense mechanism induced by streptozocin infusion during laparoscopic surgery in diabetic rats and to show the importance of regulation of diabetes for peritoneal defense mechanisms. One hundred twenty-six Sprague-Dawley male rats were allocated into six groups each consisting of 21 rats: group 1, nondiabetic sham laparotomy (control); group 2, nondiabetic pneumoperitoneum (control); group 3, uncontrolled diabetes plus sham laparotomy; group 4, controlled diabetes plus sham laparotomy; group 5, uncontrolled diabetes plus pneumoperitoneum; and group 6, controlled diabetes plus pneumoperitoneum. Diabetes was constituted by intraperitoneal infusion of one dose of 60 mg/kg streptozotocin, and diabetes was regulated (in groups 4 and 6) by subcutaneous injection of 10 IU/kg insulin in the morning and evening after the blood glucose measurements since the fourth day. Peritoneal fluid samples were taken at the zero, second, and sixth hours after sham laparotomy for groups 1, 3, and 4 and after pneumoperitoneum for groups 2, 5, and 6 on the seventh day. Total peritoneal cell count, antibacterial activity of the peritoneal fluid, and types of phagocytic cells in the peritoneal fluid were assessed. Peritoneal cell count was found to be lower in uncontrolled diabetes due to high blood glucose levels (>200 mg/dL), which led to slow migration of phagocytic cells into the peritoneum. Pneumoperitoneum had augmented the effect on phagocytic cell migration to the peritoneum compared with the sham laparotomy in controlled diabetic rats. Uncontrolled and controlled diabetes have adverse effects on peritoneal defense mechanism killing functions by interfering with the antimicrobial activity of peritoneal fluid.

Effects of pneumoperitoneum on hemodynamic and systemic immunologic responses to peritonitis in pigs.

BACKGROUND: Experimental evidence supporting the safety of laparoscopic intervention during sepsis is limited. The purpose of this study was to evaluate the effects of pneumoperitoneum on immunologic and hemodynamic responses to peritoneal sepsis. MATERIALS AND METHODS: A porcine model of peritonitis was created using an intraperitoneal autologous fecal inoculum. Pigs were then subjected to one of four procedures 24 h postinoculation (n = 6 per group): laparotomy, CO(2) laparoscopy, helium laparoscopy, and anesthesia only (1.5% isoflurane in 100% O(2), mechanical ventilation). Venous blood samples were obtained prior to inoculation, and at 24 (prior to procedure), 30, 48, 72, and 96 h postinoculation to determine white blood count (WBC) with differential, C-reactive protein (CRP), tumor necrosis factor, and bacteremia. Heart rate, end-tidal CO(2) (ETCO(2)), mean arterial blood pressure (MAP), and arterial blood gas variables were also measured at baseline and every 30 min throughout the procedure. RESULTS: Postoperative blood cultures confirmed systemic bacteremia in all groups at all time periods postinoculation. Following inoculation, WBC, band cell count, and CRP remained elevated above baseline in all groups throughout the study (P < 0.01). However, no significant differences in these parameters were observed among groups. In the CO(2) laparoscopy group, MAP, ETCO(2), and arterial pCO(2) were increased above baseline, while pH was decreased throughout the procedure (P < 0.01). CONCLUSIONS: In this animal model of peritonitis, CO(2) pneumoperitoneum induced hypercapnia, acidemia, and systemic hypertension intraoperatively, without a discernable effect on systemic immune function.

Open versus laparoscopic surgery: a comparison of natural antitumoral cellular immunity in a small animal model.

The scope of laparoscopic surgery has extended to the treatment of cancer. The immunological impact of laparoscopic surgery as compared with open surgery has not been well characterized. A paucity of information is available about differences or similarities of these two methods regarding natural antitumoral cellular immunity, namely, natural killer cell cytotoxicity. This study compared the activity of natural killer cells in rats subjected to pneumoperitoneum, open dissection of the retroperitoneum, and laparoscopic dissection of the retroperitoneum. When compared to control animals, rats subjected to pneumoperitoneum did not show any change in natural killer cell activity. Conversely, the groups of open surgery and laparoscopic surgery revealed significantly decreased natural killer cell cytotoxicity compared with controls (P < 0.0167). When the laparoscopic and the open surgical groups were compared to each other, no difference was found. In this study, both open and laparoscopic surgery had a suppressive effect upon the natural antitumoral cellular immunity. Pneumoperitoneum did not have an immune suppressive effect on natural killer cell activity. In this model, the advantages of laparoscopic surgery do not apply to natural antitumoral cellular immunity.