Indoleamine 2,3-dioxygenase mediates immune-independent human tumor cell resistance to olaparib, gamma radiation, and cisplatin.
Indoleamine 2,3-dioxygenase-1 (IDO) is an immunosuppressive molecule expressed by most human tumors. IDO levels correlate with poor prognosis in cancer patients and IDO inhibitors are under investigation to enhance endogenous anticancer immunosurveillance. Little is known of immune-independent functions of IDO relevant to cancer therapy. We show, for the first time, that IDO mediates human tumor cell resistance to a PARP inhibitor (olaparib), gamma radiation, cisplatin, and combined treatment with olaparib and radiation, 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 reduction of IDO decreased NAD+ in human tumor cells. NAD+ is essential for PARP activity and these data suggest that IDO mediates treatment resistance independent of immunity and at least partially due to a previously unrecognized role for IDO in DNA repair. Furthermore, IDO levels correlated with accumulation of tumor cells in G1 and depletion of cells in G2/M of the cell cycle, suggesting that IDO effects on 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.
Department of Microbiology and Immunology, Western University, London, Ontario, Canada.
Saman
S
Maleki Vareki
Mateusz
M
Rytelewski
Rene
R
Figueredo
Di
D
Chen
Peter J
PJ
Ferguson
Mark
M
Vincent
Weiping
W
Min
Xiufen
X
Zheng
James
J
Koropatnick
D000970:Antineoplastic Agents / Q000494:pharmacology*; D024682:BRCA2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D002453:Cell Cycle; D049109:Cell Proliferation; D002945:Cisplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005720:Gamma Rays; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D010793:Phthalazines / Q000008:administration & dosage; D010879:Piperazines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D011836:Radiation Tolerance; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; C576710:IDO1 protein, human; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D010793:Phthalazines; D010879:Piperazines; D034741:RNA, Small Interfering; D002945:Cisplatin; C531550:olaparib