Zinc protoporphyrin IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase

Richard Metz, James B. DuHadaway, Sonja Rust, David H. Munn, Alexander J. Muller, Mario Mautino, George C. Prendergast

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1864-1871
Number of pages8
JournalMolecular cancer therapeutics
Volume9
Issue number6
DOIs
StatePublished - Jun 1 2010

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Indoleamine-Pyrrole 2,3,-Dioxygenase
Immunosuppressive Agents
Immunity
Enzymes
Neoplasms
Heme
Enzyme Assays
Infection
zinc protoporphyrin
Tryptophan
Small Interfering RNA
Melanoma
Breast Neoplasms
T-Lymphocytes
Skin

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Zinc protoporphyrin IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase. / Metz, Richard; DuHadaway, James B.; Rust, Sonja; Munn, David H.; Muller, Alexander J.; Mautino, Mario; Prendergast, George C.

In: Molecular cancer therapeutics, Vol. 9, No. 6, 01.06.2010, p. 1864-1871.

Research output: Contribution to journalArticle

Metz, Richard ; DuHadaway, James B. ; Rust, Sonja ; Munn, David H. ; Muller, Alexander J. ; Mautino, Mario ; Prendergast, George C. / Zinc protoporphyrin IX stimulates tumor immunity by disrupting the immunosuppressive enzyme indoleamine 2,3-dioxygenase. In: Molecular cancer therapeutics. 2010 ; Vol. 9, No. 6. pp. 1864-1871.
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