Immunologisch basierte Wirkmechanismen der O3/O2-PP-Tumortherapie

Head and Neck Squamous Cell Carcinoma (HNSCC) is the sixth leading cancer by incidence worldwide. The papilloma virus-associated rabbit auricular VX2 tumor model of the New Zealand White (NZW) rabbit is an established animal tumor model which resembles the human HNSCC in its morphological characteristics and property for lymphogenic metastatic spread. In this study the VX2 tumor was used to characterize underlying antitumorigenic mechanisms of intraperitoneal oxidative stress following O3/O2-pneumoperitoneum (O3/O2-PP) treatment. Solid auricular VX2 tumors were induced in NZW rabbits and after reaching a defined tumor size the O3/O2-PP therapy was started. Regressive and progressive tumors were surgicaly ablated. In comparison to sham treatment the O3/O2-PP therapy resulted in a significantly higher proportion of regressing tumors. Immunohistochemical staining exhibited increased levels of CD3+ tumor infiltrating lymphocytes (TILs) in VX2 tumors under regression. RT-qPCR of 84 immunologically relevant factors showed enhanced gene expression levels of receptors involved in pattern recognition, molecules required for antigen presentation, and T cell activation as well as inflammatory mediators. Adoptive transfer of peripheral blood leukocytes (PBL) derived from animals with tumor regression into control animals with progressing tumors represented functional proof for the presence of acquired tumor resistance in the host leading to tumor regression in recipient animals. Reimplantation experiments in cured animals confirmed the acquisition of tumor resistance pointing to the presence of memory cells directed against the VX2 tumor tissue. Gene expression analyses of epidermal growth factor receptor (EGFR)-family members exhibited significant lower expression levels of EGFR, ErbB2 and ErbB3 in regressive tumors. Investigation of their localization by in situ hybridization showed increased expression of EGFR at the tumor front and a homogenous distribution of ErbB2 and ErbB3 in the entire tumor tissue. The data support the hypothesis that intraperitoneal oxidative stress (O3/O2-PP) triggers an immune mediated remission of the VX2 tumor due to upregulation of antitumorigenic immune reactions and reduction of growth factor receptors within the tumor tissue. Therefore, intraperitoneal oxidative stress could represent an effective immune mediated anti-tumor treatment not requiring ex vivo stimulation of isolated TILs. Further analyses of the local intraperitoneal O3/O2-induced immunomodulatory mechanism could help in the development of new antitumor strategies.