Abstract
LILRB4 expression in monocytic AML cells blocks T-cell activity and promotes tumor infiltration.
Major finding: LILRB4 expression in monocytic AML cells blocks T-cell activity and promotes tumor infiltration.
Mechanism: Autocrine APOE–LILRB4 signaling in monocytic AML cells mediates T-cell inhibition and tumor infiltration.
Impact: Combined targeted anti-LILRB4 therapy and immunotherapy may be efficacious in patients with monocytic AML.
Immune checkpoint blockade (ICB) therapy has been successful in patients with both solid and blood cancers; however, ICB therapy has not been efficacious in patients with leukemias. Recently, it has been shown that leukemic cells express immune-inhibitory receptors such as leukocyte immunoglobulin-like receptor B4 (LILRB4), which are expressed on monomyeloid cells. To determine whether mechanisms driving normal immune regulation promote the immune evasion and development of monocytic acute myeloid leukemia (AML), Deng, Gui, Kim, and colleagues characterized the expression of immune co-stimulatory and co-inhibitory receptors in the context of overall survival in patients with AML. LILRB4 expression was shown to be increased in patient AML cells compared to matched normal myeloid cells and negatively correlated with survival of patients with AML. LILRB4+ AML cells inhibited T-cell proliferation in vitro, and genetic or antibody-mediated ablation of LILRB4 resulted in the restoration of T-cell cytotoxicity. Expression of LILRB4 promoted AML migration in vitro and in vivo, and LILRB4 ablation inhibited mouse AML and human monocytic AML development as well as extramedullary homing and engraftment. It was shown that APOE binds to LILRB4 to drive LILRB4-mediated intracellular SHP2 and NF-κB signaling and subsequently upregulate the expression of uPAR, which promotes cancer invasion, and arginase 1 (ARG1), which suppresses T-cell proliferation. Further, addition and overexpression of either uPAR or ARG1 rescued the defective T-cell inhibition and migration ability of LILRB4 knockout AML cells. Together, these results identify and characterize the role of an immunoreceptor in regulating the tumor immune microenvironment and suggest that LILRB4 blockade may increase the efficacy of ICB in patients with monocytic AML.
Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
RSS Feeds