gms | German Medical Science

Introduction: During hyperthermic intraperitoneal chemotherapy (HIPEC), tumor cells are exposed both to cytostatic drugs and hyperthermia as well. The rationale for this treatment is an assumed synergy against malignant cells. However, this may also impact on immunological factors. We assessed effects of different cytostatic drugs (cisplatin (CCDP)/ mitomycin (MMC)) combined with or without hyperthermia on vitality and expression profiles of cell lines in vitro. Further, we evaluated effects of HIPEC treatment on circulatory regulatory T cells (Treg) inhibiting T cell immune responses in vivo.

Material and methods: Human colon and ovarian cancer cell lines were exposed to CCDP or MMP (30/ 20µg/ml) at 37°C or 42°C respectively. Cell vitality was determined at day 0/1/2/3/6 by flow cytometry after staining with annexin V and 7-AAD. RNA from three different colon cancer cell lines was isolated and analyzed using whole transcriptome arrays for consistent changes introduced by CCDP, MMC and hyperthermia such as their combinations. Blood was drawn from patients with peritoneal carcinomatosis (PC) before and after HIPEC. Circulatory mononuclear cells were analyzed for percentages of CD4+ CD25high CD127low FoxP3+ Treg by multicolor flow cytometry.

Results: Cell death introduced by cytostytic drugs and hyperthermia showed cell line dependent characteristics such as generic delayed cytostatic effects. However, respective congruent expression profiles exhibited in colon cancer cell lines showed distinct and strong differences depending on treatments with respect to CCDP/ MMC and hyperthermia. With regard to percentages of Treg in circulation patients diseased showed considerably higher frequencies as opposed to healthy donors. Nevertheless, Treg frequencies diminished consistently after HIPEC treatment in PC patients.

Conclusion: Effects of HIPEC may be dependent on individual tumor characteristics and respective cytostatic drugs used, which is underlined by pronounced differences in expression profiles introduced by different drugs. As the cytostatic effects observed in vitro cannot fully mimic effects in vivo, this may underestimate the real effects introduced by hyperthermia. Further, it is noteworthy that Treg frequencies in patients with PC are generally higher than in healthy individuals, a finding which has been correlated with poor outcome in diverse malignancies. However, Treg frequencies are diminished after HIPEC and this may create a window relevant with regard to possible combinatorial immunotherapies.