Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Microbiology and Immunology

Supervisor

Dr. James Koropatnick

Abstract

Indoleamine 2,3-dioxygenase-1 (IDO) is an immunosuppressive molecule expressed by most human tumours. IDO levels correlate with poor prognosis in cancer patients and IDO inhibitors are under investigation to enhance endogenous anticancer immunosurveillance. Little is known regarding the immune-independent functions of IDO relevant to cancer therapy. In this thesis I show, for the first time, that IDO mediates human tumour cell resistance, in a cell-autonomous fashion, to single and combination treatment with a diverse group of chemotherapy drugs and g radiation. These drugs include a PARP inhibitor (olaparib), a DNA cross-linking agent (cisplatin), a folate antimetabolite (pemetrexed), a nucleoside analogue (gemcitabine), a base excision repair inhibitor (methoxyamine), an NAD+ inhibitor (FK866) and combined treatments with olaparib and radiation and methoxyamine and pemetrexed in the absence of immune cells. Antisense-mediated reduction of IDO, alone and (in a synthetic lethal approach) in combination with antisense to the DNA repair protein BRCA2 sensitizes human lung cancer cells to olaparib and cisplatin. Antisense-mediated reduction of IDO (in a synthetic lethal approach) in combination with antisense to thymidylate synthase sensitizes human lung cancer cells to pemetrexed and 5FUdR. Antisense reduction of IDO decreased NAD+ in human tumour cells. NAD+ is essential for PARP activity and these data suggest that IDO mediates treatment resistance independent of its well- established immunomodulatory effects, and at least partially due to a previously unrecognized role for IDO in DNA repair. Furthermore, increased IDO levels correlated with the accumulation of tumour cells in G1 and depletion of cells in the G2/M phases of the cell cycle, suggesting that the effects of IDO on the cell cycle may also modulate sensitivity to radiation and chemotherapeutic agents. IDO is a potentially valuable therapeutic target in cancer treatment, independent of immune function and in combination with other therapies.


Included in

Neoplasms Commons

Share

COinS