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Background: TAM receptor tyrosine kinases—Tyro3, Axl and Mertk—and their ligands, Gas6 and Pros1, have been extensively studied for their cell-intrinsic pro-oncogenic function in cancer cells, including leukemia. However, much less is known about their indirect impact on tumor growth through their function as modulators of the immune system. In particular, no study has yet explored this aspect in the context of hematological malignancies. Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is the most aggressive human ALL subtype, in particular in adults, where it represents 30% of all ALL cases. The disease responds poorly to standard chemotherapy and has a very high risk of recurrence. Treatment relies on the use of a BCR-ABL1 tyrosine kinase inhibitor (TKI) with or without chemotherapy followed by an allogenic-SCT. Despite this intensive regimen a significant fraction (40%) of adult patients fails to achieve long-term disease-free survival, clearly pointing to an unmet clinical need. Methods: To explore the importance of TAM receptors and their ligands in the immune response against leukemia, we developed a very aggressive syngeneic model of Ph+ B-ALL. In this model, leukemia is driven by the expression of the fusion oncoprotein BCR-ABL1 and the loss of the Arf gene, often altered in human Ph+ ALL. Functional studies were carried out using small-molecule inhibitors and genetic mouse models. The latter allowed us to interrogate the importance of specific TAM receptors in defined immune cellular subsets. Lastly, we used pharmacologic inhibitors to explore the potential therapeutic benefit of targeting TAMR signaling alone or in combination with standard of care treatment (TKI) and checkpoint inhibitors. Results: Our study for the first time shows that Gas6, a high-affinity Axl ligand, promotes the establishment of an immune-suppressive milieu that contributes to the aggressive phenotype associated with Ph+ B-ALL. Importantly, Gas6 is not expressed by leukemic cells but rather produced by bone marrow associated stromal cells. Using genetic approaches, we demonstrate that Gas6 primarily acts through its high-affinity receptor, Axl, specifically on myeloid cells, to inhibit the anti-leukemic immune response. This immune-suppressive effect can be effectively blocked using an orally available selective Axl inhibitor or the genetic deletion of Axl in Csf1r expressing myeloid cells, leading to reduced leukemic burden and significantly prolonged survival of leukemia-challenged mice. In a subset of long-term survivors, progressive increase in PD1 expression limited the antileukemic effects associated with Axl deficiency, an effect that can be efficiently reverted by combination treatment with anti-PD1 checkpoint inhibitor.Mechanistically, the antileukemic effects promoted by Gas6/Axl blockade are mediated by an enhanced inflammatory response, followed by a potent adaptive immune response. This can be further potentiated by combination with standard of care therapy (i.e., TKI and chemotherapy), leading to an unprecedented cure rate of over 70%. This synergistic effect was completely abolished when the combination was evaluated in immune-compromised hosts, further emphasizing the strict immune-dependent nature of this phenotype. Conclusion: Our work uncovers a novel mechanism through which leukemic cells maintain an immune-suppressive environment by co-opting the ability of stromal cells to produce Gas6, a secreted TAM receptor ligand that dampens the ability of innate immune cells to fight leukemia. Therapeutic targeting of the Gas6/Axl axis effectively unleashes the innate immune system by promoting an enhanced proinflammatory response and engagement of a productive adaptive immune response. When combined with TKI or anti-PD1 in vivo, this treatment significantly improves the outcome of leukemia-challenged mice, leading to a remarkable cure rate of over 70%, unprecedented in this agressive model of Ph+ B-ALL. Citation Format: Irene Tirado-Gonzalez, Aleksandra Nevmerzhitskaya, Arnaud Descot, Devona Soetopo, Ewelina Czlonka, Maresa Weitmann, Carolin Wachtel, Julia Slotta-Huspenina, Christine Tran-Quang, Katharina Götze, Emily Alberto, Carla Vanina Rothlin, Jacques Ghysdael, Hind Medyouf. TAM receptors targeting unleashes antileukemic immunity and enables checkpoint blockade leading to eradication of leukemic cells [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A092.