Distinct Cell-Intrinsic and Extrinsic Consequences of TLR2 Activation Drive Pleiotropic Effects in AML Pathogenesis

Inflammation can both repress and promote tumor progression depending on the type, frequency, and combination with different therapeutic modalities. In acute myeloid leukemia (AML) generation of effector cells of the innate immune system are attenuated, suggesting that innate immune function has a critical role in leukemogenesis. Using a panel of ligands directed at the Toll-like family of pattern recognition receptors (TLRs) to induce acute inflammation in models of high-risk AML, we uncover that TLR2 ligands exert unique anti-leukemia effects distinct from other TLRs, through cell-type specific autonomous and non-autonomous mechanisms. TLR2 signaling causes non-specific inflammatory-mediated AML cell death, leukemia stem cell (LSC) reprogramming with impaired self-renewal, bi-lineage myeloid maturation, and prolonged survival. Subsequent cytokine signaling both promotes and antagonizes these AML-intrinsic effects, at least in part through G-CSF released from cells in the bone marrow microenvironment. Importantly, TLR2 is the most abundant TLR expressed in human AML regardless of ELN or mutation status, suggesting a key role in human disease. Together, these data indicate functional interplay of innate immune signaling between AML cells and the microenvironment during acute inflammation directly impacts leukemia progression. Overall design: CITEseq: B6: CD45.1 mice were transplanted with Dnmt3a-/+Flt3ITD/ITD;Mx1-Cre AML. Mice were treated 2 weeks later with either 100µL PBS or 100µg Pam3CSK4. 24 hours after treatment, mice were sacrificed and bone marrow cells were isolated. Cells were FACs sorted for either CD45.2+Lin-CD117+ (HSPC) or CD45.2+CD11b+ (mature) cells