Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy

• Published in: International journal of molecular sciences 2019-01, Vol.20 (3), p.482
• Main Authors: Schillingmann, Damaris A, Riese, Sebastian B, Vijayan, Vijith, Tischer-Zimmermann, Sabine, Schmetzer, Helga, Maecker-Kolhoff, Britta, Blasczyk, Rainer, Immenschuh, Stephan, Eiz-Vesper, Britta
• Format: Article
• Language: English
• Subjects: Antigen (tumor-associated); Antigen-specific T cells; Antigens; Cancer; Cancer immunotherapy; Cytokines; Cytomegalovirus; Cytotoxicity; Enrichment; Enzymatic activity; Enzyme-linked immunosorbent assay; Flow cytometry; Genotype & phenotype; Graft-versus-host reaction; Heme; Heme oxygenase (decyclizing); heme oxygenase 1 (HO-1) inhibition; Immunotherapy; Leukemia; Leukocytes (mononuclear); Lymphocytes; Lymphocytes T; Oxygenase; Peptides; Peripheral blood mononuclear cells; Stem cell transplantation; Tumors; Wilms tumor protein-1 (WT1), acute myeloid leukemia (AML); γ-Interferon
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20030482

Wilms tumor protein-1 (WT1) is an attractive target for adoptive T-cell therapy due to its expression in solid tumors and hematologic malignancies. However, T cells recognizing WT1 occur in low frequencies in the peripheral blood of healthy donors, limiting potential therapeutic possibilities. Tin mesoporphyrin (SnMP) is known to inhibit heme oxygenase-1 (HO-1), which has been shown to boost the activation and proliferation of human virus-specific T cells. We analyzed the influence of this effect on the generation of WT1-specific T cells and developed strategies for generating quantities of these cells from healthy donors, sufficient for adoptive T-cell therapies. HO-1 inhibition with SnMP increased WT1-specific T-cell frequencies in 13 (26%) of 50 healthy donors. To assess clinical applicability, we measured the enrichment efficiency of SnMP-treated WT1-specific T cells in response to a WT1-specific peptide pool and a HLA-A*02:01-restricted WT1 peptide by cytokine secretion assay. SnMP treatment resulted in a 28-fold higher enrichment efficacy with equal functionality. In conclusion, pharmacological inhibition of HO-1 activity with SnMP results in more efficient generation of functionally active WT1-specific T cells. This study demonstrates the therapeutic potentials of inhibiting HO-1 with SnMP to enhance antigen-specific T-cell responses in the treatment of cancer patients with WT1-positive disease.