Abstract
Peritoneal metastasis (PM) arises from different gastrointestinal cancers and ovarian cancer. The most common primary tumor metastasizing to the peritoneum is colorectal cancer (CRC). The treatment of these patients suffering with PM depends on several factors including the extent of the disease in the peritoneal cavity. In case of a limited disease, cytoreductive surgery (CRS) in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) can be indicated. The concept of this treatment approach is to resect the visible tumor mass during CRS and eradicate remnant microscopic tumors via the HIPEC application. One of the two different drug regimens applied for CRC-PM are either the combination of Mitomycin C and Doxorubicin or Oxaliplatin alone. The median overall survival (OS) of patients treated with CRS/HIPEC is roughly 50 months with some long-term survivors, surviving up to 8 years. Why some patients respond better and show long-term survival remains unclear. Clinical studies indirectly suggest a better tumor control probably via the immune system most likely due to the induction of chemotherapeutics-mediated protective immune reactions. In this thesis, the direct and indirect impact of HIPEC treatment on the immune system to explain induction of tumor-specific immunity were explored. Using patient samples, a systemic inflammatory response after HIPEC and an impaired accuracy of commonly used inflammatory parameters in clinics to diagnose postoperative infectious complications were examined. Furthermore, with the specific analysis of paired (primary tumors and metastatic lesions) PM patient samples, a significant longer disease free survival (DFS) and overall survival (OS) was noticed in the patient group with a higher number of intraepithelial CD8+ T-cells in the PM tumor than with a low number. This was the basis to further investigate HIPEC-mediated effects on CD8+ T-cell infiltration in a murine PM model. The results of these experiments illustrated, that the efficacy of HIPEC was dependent on the function and presence of CD8+ T-cells. Using colorectal cancer cell lines and patient- derived tumor organoids, it was noted that heated chemotherapy (in-vitro HIPEC treatment) treatment induced immunogenic changes via enhanced expression of MHC-class I molecules and cancer testis antigens (CTA). Such immunogenic changes initiated the maturation of monocyte-derived dendritic cells and subsequently the production of intracellular IFN- by CD8+ T-cells. Overall, the work presented in this thesis might help patients suffering with PM by identifying post operation infections at an early stage using additional markers, overall reducing disease and surgery related complications. The work performed using experimental models show that HIPEC treatment seems to enhance immunogenicity of cancer cells making that can activate CD8+ T-cells. This mechanistic finding suggests that in the future patients with PM might survive better if treated with immunotherapies after HIPEC treatment as immunotherapies are known to provide sustained T-cells activity.
Roth, Lilian