Zinc protoporphyrin IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase.
The tryptophan catabolic enzyme indoleamine 2,3-dioxygenase (IDO) has emerged as an important driver of immune escape in a growing number of cancers and cancer-associated chronic infections. In this study, we define novel immunotherapeutic applications for the heme precursor compound zinc protoporphyrin IX (ZnPP) based on our discovery that it is a potent small-molecule inhibitor of IDO. Inhibitory activity was determined using in vitro and in-cell enzyme assays as well as a novel in vivo pharmacodynamic system. An irreversible mechanism of inhibition was documented, consistent with competition for heme binding in newly synthesized cellular protein. siRNA methodology and an IDO-deficient mouse strain were used to verify the specificity of ZnPP as an IDO inhibitor. In a preclinical model of melanoma, ZnPP displayed antitumor properties that relied on T-cell function and IDO integrity. ZnPP also phenocopied the known antitumor properties of IDO inhibitors in preclinical models of skin and breast carcinoma. Our results suggest clinical evaluation of ZnPP as an adjuvant immunochemotherapy in chronic infections and cancers in which there is emerging recognition of a pathophysiologic role for IDO dysregulation.
New Link Genetics Corporation, Ames, Iowa, USA.
Richard
R
Metz
James B
JB
Duhadaway
Sonja
S
Rust
David H
DH
Munn
Alexander J
AJ
Muller
Mario
M
Mautino
George C
GC
Prendergast
D000818:Animals; D002460:Cell Line; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects*; D007109:Immunity / Q000187:drug effects*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D051379:Mice; D009369:Neoplasms / Q000201:enzymology* / Q000276:immunology*; D011524:Protoporphyrins / Q000494:pharmacology*
D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011524:Protoporphyrins; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1