Abstract
Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. It triggers the release of type I interferons (IFN) and proinflammatory cytokines inducing an adaptive cellular immune response. We investigated the therapeutic potential of systemic RIG-I activation by short 5′-triphosphate-modified RNA (ppp-RNA) for the treatment of acute myeloid leukemia (AML) in the syngeneic murine C1498 AML tumor model. ppp-RNA treatment significantly reduced tumor burden, delayed disease onset and led to complete remission including immunological memory formation in a substantial proportion of animals. Therapy-induced tumor rejection was dependent on CD4+ and CD8+ T cells, but not on NK or B cells, and relied on intact IFN and mitochondrial antiviral signaling protein (MAVS) signaling in the host. Interestingly, ppp-RNA treatment induced programmed death ligand 1 (PD-L1) expression on AML cells and established therapeutic sensitivity to anti-PD-1 checkpoint blockade in vivo. In immune-reconstituted humanized mice, ppp-RNA treatment reduced the number of patient-derived xenografted (PDX) AML cells in blood and bone marrow while concomitantly enhancing CD3+ T cell counts in the respective tissues. Due to its ability to establish a state of full remission and immunological memory, our findings show that ppp-RNA treatment is a promising strategy for the immunotherapy of AML.
Highlights
These author contributed : Michael Ruzicka and Lars M
To asses the in vivo efficacy of Retinoic acid-inducible gene-I (RIG-I)-based immunotherapy of acute myeloid leukemia (AML) we utilized the C1498 model, a murine AML cell line on C57BL/6 background classified as acute myelomonocytic leukemia [30], which was implanted in immune competent syngeneic mice
In order to investigate the overall therapeutic potential of systemic ppp-RNA treatment with regard to AML, we inoculated C57BL/6 mice with 1 × 106 GFP expressing C1498 AML cells (C1498-GFP) via tail vein injection. ppp-RNA was complexed with in vivo-jetPEI in order to protect it from nuclease digestion and enable cytoplasmic delivery of ppp-RNA
Summary
These author contributed : Michael Ruzicka and Lars M. By applying an exogenous short ppp-RNA, a viral infection can be mimicked, allowing direction of the immune response towards otherwise altered or potentially harmful targets, such as cancerous cells. While this approach has shown survival benefits in different solid tumor models [4, 6, 7, 20], the treatment efficacy of RIG-I ligands for non-solid tumors in vivo remains elusive. Since mainly affecting the bone marrow and blood, we expected AML to be more susceptible to intravenous (i.v.) treatment with ppp-RNA, subsequent systemic cytokine responses and immune cell-mediated cytotoxicity than solid tumors. We explore the responsiveness of AML to ppp-RNA treatment alone and in combination with anti-PD-1 blocking antibodies in the murine syngeneic C1498 AML model and in immune-reconstituted humanized mice with patientderived xenografted (PDX) AML cells
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