MPN-053: Tumor-Intrinsic IRAKI-Dependent Inflammation Signaling Induces MDSC to Establish Immune Evasion in FGFRI-Driven Hematological Malignancies

Context: Stem cell leukemia/lymphoma syndrome (SCLL) presents as a myeloproliferative disease that can progress to acute myeloid leukemia and is associated with the coincident development of B-cell and T-cell lymphomas. SCLL is driven by the constitutive activation of FGFR1, as a result of chromosome translocations, with poor outcome. Objective: In this study, we use this model to investigate how FGFR1 drives IRAK1-dependent inflammatory signaling in the modulation of antitumor immunity. Design: CRISPR/Cas9 approaches were used to generate SCLL cells null for IRAK1, which were introduced into syngeneic hosts through tail vein injection. Development of the disease and changes in immune cell composition were monitored using flow cytometry. Results: In SCLL, FGFR1 activation silences miR-146b-5p through DNMT1-mediated promoter methylation, which derepresses the downstream target IRAK1. IRAK1 knockout (KO) in SCLL cells leads to the loss of typical rapid progression when xenografted into immunocompetent mice, and the mice remained disease-free. IRAK1 in this system has no effect on cell cycle progression or apoptosis, and robust growth of the KO cells in immunodeficient mice suggested an effect on immune surveillance. Depletion of T-cells in immunocompetent mice restored leukemogenesis of the KO cells. Analysis of the immune cell profile in mice transplanted with the IRAK1-null cells shows that there is a reduction in levels of myeloid-derived suppressor cells (MDSCs) with a concomitant increase in CD4+/CD8+ T-cell levels. Immunoprofiling of a panel of secreted cytokines and chemokines showed that activation of INF-γ is specifically impaired in the KO cells. In vitro and in vivo expression assays and engraftment into IFNGR1-null mice showed SCLL leukemia cells produced INF-γ, not only promoting intrinsic PD-L1 expression but also participating in the induction of MDSCs to establish immune evasion. Inhibition of IRAK1 using pacritinib suppresses leukemogenesis with impaired induction of MDSCs and attenuated suppression of CD4+/CD8+ T-cells. Conclusions: IRAK1 orchestrates a previously unknown FGFR1-directed immune escape mechanism in SCLL, through induction of IFN-γ, and targeting IRAK1 may provide a means of suppressing tumor growth in this syndrome by restoring immune surveillance. This work was supported by grant CA076167 from the National Institutes of Health.