Oncofetal RNA-binding proteins IGF2BP suppress innate immunity signaling pathways in leukemia stem cells

Abstract

Abstract Activation of innate inflammatory signaling and tumor-specific antigen presentation in cancerous cells lays a foundation for anticancer immunotherapies. Understanding mechanisms of tumor-intrinsic pattern recognition receptors (PRR) stimulation and interferon-stimulated genes (ISGs) expression in cancer cells is critical for overcoming immune evasion and unresponsiveness of so-called “cold” tumors to immunotherapies. Here, we demonstrate that Insulin Growth Factor 2 Binding Proteins (IGF2BP1, 2, and 3 paralogs), which are upregulated in various types of human malignancies including myeloid and lymphoblastic leukemia, suppress the activity of RNA-sensing PRRs and downstream ISRE- and NF-kB-controlled transcription. IGF2BPs display a strong inhibitory effect on RIG-I signaling, which is significantly activated upon IGF2BP1-3 downregulation with and without RIG-I stimulation. The inhibitory effect of IGF2BPs on innate immunity signaling is maximized in established cell lines and patient-derived leukemic cells expressing three IGF2BP paralogs, which correlates with inferior overall survival in AML and the previously described role of IGF2BPs in maintaining leukemia stem cell phenotype. Oncogenic transformation of human and mouse cells with SV-40 T large antigen induces de novo expression of IGF2BP paralogs, which suppress the expression of cytosolic RNA sensors in these cells. Genetic inhibition of IGF2BP1-3 significantly increases expression of interferon-stimulated genes (ISG), including MHC class I. In summary, we demonstrate that (i) oncofetal RNA-binding proteins IGF2BP suppress innate immunity signaling pathways downstream of pattern recognition receptors; (ii) the inhibitory role of IGF2BPs at least partially conveyed through IGF2BP-mediated support of negative regulators of RIG-I signaling (e.g., ubiquitin ligases TNFAIP3, TRIM38); (iii) inhibition of IGF2BPs in combination with PRR agonists (RIG-I, TLR3, TLR8) is a promising approach for anti-AML immunotherapies; (iv) combinatory targeting IGF2BPs with other post-transcriptional regulators of interferon signaling, e.g., ELAV1/HuR, leads to increased anti-leukemia effect.