AXL Inhibition in Macrophages Stimulates Host-versus-Leukemia Immunity and Eradicates Naïve and Treatment-Resistant Leukemia

Abstract

Acute leukemias are systemic malignancies associated with a dire outcome. Due to low immunogenicity, leukemias display a remarkable ability to evade immune control and are often resistant to checkpoint blockade. Here, we discover that leukemia cells actively establish a suppressive environment to prevent immune attacks by co-opting a signaling axis that skews macrophages towards a tumor promoting tissue repair phenotype, namely the GAS6/AXL axis. Using aggressive leukemia models, we demonstrate that ablation of the AXL receptor specifically in macrophages, or its ligand GAS6 in the environment, stimulates anti-leukemic immunity and elicits effective and lasting NK-and T-cell dependent immune response against naive and treatment resistant leukemia. Remarkably, AXL deficiency in macrophages also enables PD1 checkpoint blockade in PD1-refractory leukemias. Lastly, we provide proof-of-concept that a clinical grade AXL inhibitor can be used in combination with standard of care therapy to cure established leukemia, regardless on AXL expression in malignant cells.

Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer

“…Axl is also expressed by bone marrow-derived cells, dendritic cells, monocytes, natural killer cells, and platelets [36][37][38][39][40][41][42]. A study by Tirado-Gonzalez and colleagues also demonstrated that Axl-expressing leukemia-associated macrophages contribute to immune suppression and impair the functions of NK-and T-cell-mediated tumor cell killing [43].…”

Translating recent advances in the pathogenesis of acute myeloid leukemia to the clinic

“…However, these promising results need to be validated in the ongoing randomized placebo-controlled phase III trial (NCT04313881). Besides targeting CD47, ablation of the AXL receptor in macrophages has been shown to enable NK cell- and T-cell-mediated antitumor immune responses and to restore sensitivity to PD1 inhibition in preclinical leukemia models ( Tirado-Gonzalez et al 2021 ).…”

Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer

“…High levels of MERTK and/or AXL have also been implicated in drug resistance and radioresistance [ 54 , 55 , 60 , 69 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ]. Increased MERTK or AXL expression in NSCLC correlated with chemotherapy resistance [ 51 , 66 , 70 , 87 , 88 , 89 ].…”

“…LPS challenge led to over-produced TNFα in Mertk kd mice, which lack the tyrosine kinase signaling domain, due to hyper-activation of NFκB [ 45 , 153 ]. Inhibition of MERTK by knockout of Mertk in mice, neutralization of TAM kinase signaling using a recombinant MERTK-Fc protein as a ligand sink or a GAS6 blocking antibody, and knockout of AXL in macrophages also impaired M2-macrophage anti-inflammatory phenotypes, decreased immunosuppressive IL-10 production, and increased pro-inflammatory IL-12 release [ 86 , 143 , 154 , 155 ]. These cytokine alterations lead to expansion of anti-tumor CD8 + T lymphocytes and inhibition of tumor growth and metastasis ( Figure 3 B).…”

“…Cyclic GAMP-AMP synthase (cGAS)-STING signaling in immune cells is a key determinant for therapeutic efficacy of immune checkpoint inhibitors [ 182 , 184 ]. Indeed, blockade of MERTK or AXL using a specific antibody or treatment with sitravatinib or R428 synergized with anti-PD-1 or anti-PD-L1 therapy to enhance anti-tumor immune responses [ 86 , 162 , 168 ].…”