Targeting of indoleamine 2,3-dioxygenase in inflammation mediated by photodynamic therapy of cancer
Malgorzata Wachowska1,2, Joanna Stachura1,3, Angelika Muchowicz1*
1Department of Immunology, Medical University of Warsaw, Warsaw, Poland;
2Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, MUW, Poland.
3School of Molecular Medicine, MUW, Poland.
Photodynamic therapy (PDT) is a clinically approved, therapeutic procedure used for selective targeting of solid tumors. PDT involves the administration of photosensitizer, which is subsequently irradiated with a laser light. PDT induces oxidative stress and massive generation of damage-associated molecular patterns in the tumor area that elicits acute inflammatory response. Thus, PDT combined with immunomodulative drug can be very effective and lead to recovery through activation of specific antitumor immune response. Indoleamine 2,3-dioxygenase (IDO), an enzyme that transforms tryptophan into kynurenine, generates a tumor-permissive environment . Due to extensive role of IDO in the induction of immunosuppressive environment, this enzyme becomes an attractive target for drug development.
In this project we address the role of IDO in the mitigation of the immune response triggered by PDT and investigate whether inhibition of IDO activity allows for development of improved antitumor response to this treatment.
All experiments were done in orthotopic 4T1 and E0771 model of mouse breast cancer and involved enzymatic assays, molecular biology techniques and flow cytometry.
Our first experiments show that PDT significantly augments IDO activity in tumors and tumor draining lymph nodes. Moreover, induction of IDO activity correlates with increase of T regulatory lymphocytes percentage. Surprisingly, administration of IDO inhibitors leads to animals death three days post PDT. Therefore, experiments carried out in this project will investigate significant role of IDO in reduction of tissue damage during acute inflammation in the tumor area, damaged by oxidative stress.
Project is supported by NCN UMO-2014/13/D/NZ6/01080 and the STREAM funded by European Union’s Horizon No 692180