Forsøksdyr: Immunologisk antitumor effekt ved hyperbar adjuvant oksygenbehandling


Godkjenningsdato 09.02.2018

Antitumor T- and natural killer (NK) cells are avoiding hypoxic conditions and their activity is inhibited in extracellular adenosine-rich tumor microenvironments. Adenosine inhibits immune cell activity through A2A adenosine receptors stimulated endogenous cyclic AMP production and activation of protein kinase A (PKA). We have shown that hyperbaric oxygen treatment (HBOT) of mice inoculated with triple negative breast cancer cells (Eo771/basal-like/triple negative- from B57/BL mice) develop severe solid tumors within 7-10 at point they will be left untreated or treated by HBOT. After 10 to 12 days the tumor will develop further in the absence but not presence of HBOT. Moreover, we have shown that the effect of HBOT is reduced by approximately 50 % in mice depleted for T- and B cells (RAG -/- mice) implying that HBOT may be used as an adjuvant treatment to elicit antitumor immune cell activity. We have recently, developed a mouse strain on a C57BL/6 background which is genetically null-mutated for the catalytic subunit Cbeta2 of PKA (Cbeta2 KO) and shown that these mice are hyper sensitive to systemic inflammation. Breeding of these mice have already been approved by Matilsynet (FOTS # 8549) and they are used in experiments on collagen induced rheumatoid arthritis (CIA, FOTS # 8744). In the present project we wish to inoculate the Cbeta2 KO mice with triple negative breast cancer cells and study tumor development in the presence and absence of HBOT. To investigate the mechanism of antitumor and HBOT we will inoculate wild type (wt) C57BL/6 mice and wt C57BL/6 mice depleted for NK cells by antibodies as well as immune deficient RAG -/-. To control for immune depleted mice results we ail also introduce another well characterized strain of immunodeficient mice the so-called severe combined immunodeficiency (SCID) mice strains. In all experimental setups the mice will be euthanize after 7-10 + 10-12 days (total length of treatment between 17 and 22 days) and animals sampled for blood/serum, immune tissues tumor and non-tumor tissues. All samples will be stored in a proper way to avoid vast of valuable experimental samples.