Description

Blocking LILRB signaling impedes cancer development and targets immune checkpoints

Mi Deng¹, Xun Gui², Zhiqiang An², and Cheng Cheng Zhang^{1, *}

¹ Department of Physiology, UT Southwestern Medical Center, Dallas, TX 75390

² Texas Therapeutics Institute, Houston, TX 77030

^* Corresponding author

Targeted therapy induces rapid tumor regression, whereas immunotherapy achieves long-lasting anti-tumor effects. Ideal molecular targets enable the combination of the strengths of targeted therapy and immunotherapy. Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1-5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs that recruit protein tyrosine phosphatases and contribute to immune evasion by tumors. Recent studies by our and other laboratories found that LILRBs have dual concordant roles in tumor biology – as immune checkpoint molecules and as tumor-sustaining factors ^1,2,3,4. Here we show that LILRB4, a surface marker for monocytic acute myeloid leukemia, sustains leukemia development. We identified a potential ligand for LILRB4, which activates LILRB4-mediated signaling and supporting migration of AML cells to the microenvironment in internal organs. Further analyses revealed the downstream signalling responsible for the ligand induced tumor cell migration. Inhibition of LILRB4 signaling by LILRB4 blocking antibodies eliminated AML development through direct tumor targeting, disruption of retention of leukemia cells in the microenvironment, and immune checkpoint inhibition. LILRB4 thus represents a novel target for treating monocytic AML and perhaps solid cancer.

¹Zheng, J., et al. Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development. Nature 485, 656-660 (2012).

²Kang, X., et al. The ITIM-containing receptor LAIR1 is essential for acute myeloid leukaemia development. Nat Cell Biol 17, 665-677 (2015).

³Deng, M., et al. A motif in LILRB2 critical for Angptl2 binding and activation. Blood 124, 924-935 (2014).

⁴Kang, X., et al. Inhibitory leukocyte immunoglobulin-like receptors: Immune checkpoint proteins and tumor sustaining factors. Cell Cycle 15, 25-40 (2016).