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The RNA-binding Protein HuR in Cancer Immune Evasion: Mechanisms and Therapeutic Implications
Zhang, Qi
Zhang, Qi
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Abstract
RNA-binding protein (RBP) HuR is upregulated in multiple types of cancer and the elevated HuR is associated with high-grade tumors and poor clinical outcomes. HuR forms a complex network of interactions with target mRNAs through the recognition and binding to the adenylate-uridylate-rich elements (AU-rich elements; AREs) in their 3′-untranslated region (3′-UTR). By regulating the expression of proto-oncogenes, cytokines, and other regulatory proteins involved in various cancer hallmarks, HuR promotes tumorigenesis and cancer progression.Cancer immunotherapy, particularly the immune checkpoint blockade (ICB) represents a revolutionary advance in cancer treatment. However, only a subset of patients responds to ICB. Response rates to ICB in breast cancer, lung cancer, and prostate cancer patients are notably low. ICB targeting Programmed cell death-1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) has greatly improved clinical outcomes in diverse human cancers. However, a more thorough understanding of the mechanisms underlying low immunogenicity in these tumors is crucial to address remaining issues, including the low objective response rates in patients.In this study, we investigate the involvement of HuR in T cell activation and demonstrated that HuR knockout in cancer cells reduced PD-L1 proteins and enhanced T cell activation. We identified HuR as a novel regulator of PD-L1 and CD147 by directly binding to the 3′-UTR of their mRNA, thereby promoting their stability. Given the immunosuppressive functions of PD-L1 and CD147 in cancer, we hypothesized that functional inhibition of HuR could be a promising approach to enhance ICB efficacy. We repurposed the anti-helminthic drug niclosamide as a HuR inhibitor and discovered that it decreased PD-L1 protein levels and glycosylation by inhibiting the nucleo-cytoplasmic translocation of HuR. Niclosamide enhanced T cell-mediated killing of cancer cells and significantly improved the efficacy of anti-PD-1 immunotherapy in breast and lung syngeneic animal tumor models. To further explore the role of HuR in cancer immune evasion through CD147 regulation, we developed a HuR-specific small molecular inhibitor, KH-39, which disrupts the interaction between HuR and its target mRNAs. KH-39 effectively inhibits CD147 expression and its associated cytokine IL-6. We established a combination strategy using HuR inhibitor KH-39 and anti-PD-1 antibody to enhance the ICB response rate in a murine breast cancer model. The combination approach demonstrated substantial tumor growth inhibition and significantly improved overall survival compared to the single-agent treatments. In conclusion, this dissertation research expands our understanding of the biological role of HuR in tumor immune evasion. It provides a strong proof-of-principle of targeting HuR to modulate its downstream signaling to enhance the response of ICB immunotherapy, particularly in immune “cold” cancers.
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Date
2023-01-01
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University of Kansas
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Keywords
Biology, Cellular biology, Molecular biology, breast cancer, CD147, HuR, immune evasion, immunotherapy, PD-L1