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

Damaris Schillingmann,Rainer Blasczyk,Stephan Immenschuh,Helga Schmetzer,Vijith Vijayan,Sebastian Riese,Sabine Tischer-Zimmermann,Britta Eiz-Vesper,Britta Maecker-Kolhoff

doi:10.3390/ijms20030482

Damaris Schillingmann, Rainer Blasczyk + Show 7 more

Open Access

https://doi.org/10.3390/ijms20030482

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Abstract

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.

Highlights

Decreased relapse in leukemia patients after hematopoietic stem cell transplantation (HSCT) with non-T-cell-depleted allografts versus depleted allografts [1] may be attributed to the graft-versus-leukemia (GvL) potential of T lymphocytes
The numbers of TCM and TEM were higher on day 6 than on day 0, but stimulation with SnMP did not lead to significant alteration of the T-cell phenotype in the CD3+, CD8+, and CD4+ T-cell populations (Figure 1A)
We observed that the pharmacologic agent SnMP inhibits the enzymatic activity of heme oxygenase-1 (HO-1), resulting in the increased activation and proliferation of human virus-specific T cells [23]

Summary

Introduction

Decreased relapse in leukemia patients after hematopoietic stem cell transplantation (HSCT) with non-T-cell-depleted allografts versus depleted allografts [1] may be attributed to the graft-versus-leukemia (GvL) potential of T lymphocytes. Evidence shows that a decrease in circulating malignant cells is strongly associated with a decrease in WT1-encoding mRNA levels as well as a reduced risk of relapse and prolonged disease-free survival [10,11]. This makes WT1 an attractive target for adoptive immunotherapy. CD8+ cytotoxic T-lymphocytes (CTLs) specific for WT1 occur in cancer patients as well as in low frequencies in healthy donors [10,12]

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