TAM-family tyrosine kinases (TYRO3, AXL and MERTK) are potential cancer therapeutic targets. In previous studies MERTK inhibition in the immune microenvironment was therapeutically effective in a B-cell acute leukemia (B-ALL) model. Here, we probed anti-leukemia immune mechanisms and evaluated roles for TYRO3 and AXL in the leukemia microenvironment. Host Mertk knock-out or MERTK inhibitor MRX-2843 increased CD8α⁺ dendritic cells (DCs) with enhanced antigen-presentation capacity in the leukemia microenvironment and inhibited leukemogenesis. High MERTK or low DC gene expression were associated with poor prognosis in pediatric ALL patients, indicating the clinical relevance of these findings. MRX-2843 increased CD8⁺ T-cell numbers and prevented induction of exhaustion markers, implicating a DC – T-cell axis. Indeed, combined depletion of CD8α⁺ DCs and CD8⁺ T-cells was required to abrogate anti-leukemia immunity in Mertk^–/– mice. Tyro3^–/– mice were also protected against B-ALL, implicating TYRO3 as an immunotherapeutic target. In contrast to Mertk^–/– mice, Tyro3^–/– did not increase CD8α⁺ DCs with enhanced antigen-presentation capacity and therapeutic activity was less dependent on DCs, indicating a different immune mechanism. Axl^–/– did not impact leukemogenesis. These data demonstrate differential TAM kinase roles in the leukemia microenvironment and provide rationale for development of MERTK and/or TYRO3-targeted immunotherapies.

TAM 家族酪氨酸激酶（TYRO3、AXL 和 MERTK）是潜在的癌症治疗靶点。在之前的研究中，免疫微环境中的 MERTK 抑制在 B 细胞急性白血病 (B-ALL) 模型中具有治疗效果。在这里，我们探讨了抗白血病免疫机制并评估了 TYRO3 和 AXL 在白血病微环境中的作用。宿主Mertk敲除或 MERTK 抑制剂 MRX-2843 增加了 CD8α ⁺树突状细胞 (DC)，增强了白血病微环境中的抗原呈递能力，并抑制了白血病发生。高MERTK或低 DC 基因表达与儿科 ALL 患者的不良预后相关，表明这些发现的临床相关性。 MRX-2843 增加了 CD8 ⁺ T 细胞数量并阻止了衰竭标记物的诱导，这表明 DC - T 细胞轴。事实上，需要联合消除 CD8α ⁺ DC 和 CD8 ⁺ T 细胞才能消除Mertk ^–/–小鼠的抗白血病免疫力。 Tyro3 ^–/–小鼠也能免受 B-ALL 的侵害，这表明 TYRO3 作为免疫治疗靶点。与Mertk ^–/–小鼠相比， Tyro3 ^–/–并没有增加 CD8α ⁺ DC，同时增强了抗原呈递能力，并且治疗活性对 DC 的依赖性较小，这表明了不同的免疫机制。 Axl ^–/–不影响白血病发生。这些数据证明了 TAM 激酶在白血病微环境中的不同作用，并为开发 MERTK 和/或 TYRO3 靶向免疫疗法提供了理论基础。