https://orcid.org/0000-0002-8787-6616
Key Points
TLR2 agonism suppresses leukemogenesis across multiple AML genotypes by functional reduction of leukemia stem cells.
Diminished leukemia stem cell function is associated with TLR2-mediated cell-intrinsic upregulation of MHCII.
The consequences of activated innate immune signaling in acute myeloid leukemia (AML) is not well understood. Using ligands directed at the Toll-like family receptors (TLR) in models of high-risk AML, we uncover that TLR2 ligands exert unique anti-leukemic effects that are distinct from other TLRs. While TLR2 signaling broadly induces inflammatory gene expression in AML cells, at the single cell level, cell-type-dependent, divergent transcriptional responses coordinate cellular outputs of proliferation, differentiation, cell death, and activation of immune cell function. TLR2 ligands were the only TLR agonists capable of extending survival of AML-bearing mice through leukemia stem cell (LSC) reprogramming that elevated MHC class II surface expression and ultimately impaired self-renewal. We find that the co-expression of TLR2 and MHCII genes is associated with better overall survival in AML patients, which is consistent with our observations of activated TLR2 signaling in mice. These data reveal functional TLR2 signaling critically antagonizes leukemogenesis and emphasizes a role for TLR2 agonism in AML.
