Dataset Information

Auranofin Fosters Regulatory T Cell Expansion and Augmented Tumor Burden in Mice

ABSTRACT: Auranofin, an FDA-approved antirheumatic drug, has been reported to have anti-tumoral properties but its immunological effects and significance are not well understood. This study is the first to report auranofin-induced regulatory T cell (Treg) expansion. In a mouse model with B16F10 melanoma, auranofin treatment surprisingly resulted in increased lung tumor coverage, elevated serum IL-10 levels, and a higher frequency of FOXP3+ CD44+ CD4 T cells in the spleen compared to vehicle controls. We also noted significant differences in the relative proportions of antigen presenting cells (APCs), namely, B cells and dendritic cells (DCs). To determine if auranofin promotes Treg expansion independently of tumor-specific antigens or tumor burden, we stimulated T cell receptors ex vivo in lymph node cultures from naïve mice using anti-CD3ε/CD28 in the presence or absence of auranofin. Auranofin-treated cultures showed significantly higher Treg frequencies than controls. This phenomenon was also observed in peripheral blood mononuclear cell (PBMC) cultures from healthy donors. Results from auranofin and a specific thioredoxin reductase 1 (TRXR1) inhibitor, TRi-1, suggest that NRF2 activation through TRXR1 blockade may promote Treg expansion and immune suppression in both mice and humans. By using NCF1 deficient mice conditionally expressing functional NCF1, we found that B cell or DC specific ROS was sufficient in augmenting B16F10 tumor burden and were comparable to TRXR1 inhibitor treatment in NCF1 mutant and wild type mice. These results suggest elevated TRXR1 inhibitor induced ROS levels in APCs could trigger Treg expansion. Finally, these findings provide a rationale for the divergent anti-tumoral responses observed in auranofin-treated immunocompetent versus immunocompromised cancer models. Given the ongoing clinical trials exploring auranofin as an anti-cancer agent, this study could have clinical significance.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

SUBMITTER: Christian Beusch