Journal of experimental & clinical cancer research : CR · 2026
NRGN inhibits CD8⁺ T cell effector function by downregulating MHC-I expression through the FMR1-IRF8 axis in hepatocellular carcinoma.
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Ye Dongjie, Qiu Jiacheng, Yang Haoyi, Wu Jinqiao, Zhang Xinyu, Zhang Zhu, Wu Hao, Yao Yuxin, Wang Xiaoqian, Tang Nanhong
Аннотация
BACKGROUND: Neurogranin (NRGN) has been extensively studied as a neuron-enriched synaptic regulatory protein, yet its function in cancer remains largely unexplored. Immune evasion driven by defective antigen presentation and CD8⁺ T cell dysfunction is a hallmark of hepatocellular carcinoma (HCC). This study aimed to determine whether NRGN contributes to immune escape in HCC and to elucidate its underlying molecular mechanism.
METHODS: NRGN expression and clinical relevance were analyzed in public datasets and validated in HCC tissues. Transcriptomic and enrichment analyses assessed antigen presentation. Gain- and loss-of-function experiments were performed in human and murine HCC cells, while orthotopic and subcutaneous models with CD8⁺ T cell exhaustion, β2M knockout, and H-2Kb blockade evaluated immune dependence in vivo. RNA stability, RNA pulldown, RIP, co-immunoprecipitation, ubiquitination, and luciferase assays were conducted to define the molecular mechanisms.
RESULTS: NRGN was significantly upregulated in HCC and associated with advanced stage and poor survival, correlating inversely with GZMB⁺ CD8⁺ T cell infiltration. NRGN knockdown enriched MHC-I antigen presentation pathways and restored MHC-I/β2M expression, tumor cell surface antigen presentation, and CD8⁺ T cell cytotoxicity. In vivo, NRGN silencing suppressed tumor growth and prolonged survival in a CD8⁺ T cell-dependent manner, effects reversed by β2m deletion or H-2Kb blockade. Mechanistically, NRGN downregulated IRF8 by reducing its mRNA stability through FMR1 and stabilizing FMR1 protein via inhibition of MYCBP2-mediated ubiquitination, thereby sustaining suppression of antigen presentation.
CONCLUSIONS: NRGN suppresses antigen presentation via the FMR1-IRF8-MHC-I axis, thereby impairing CD8⁺ T cell-specific effector functions and promoting immune evasion in HCC. Modulation of the NRGN-IRF8-MHC-I axis could represent a potential strategy for improving immunotherapeutic responses.
METHODS: NRGN expression and clinical relevance were analyzed in public datasets and validated in HCC tissues. Transcriptomic and enrichment analyses assessed antigen presentation. Gain- and loss-of-function experiments were performed in human and murine HCC cells, while orthotopic and subcutaneous models with CD8⁺ T cell exhaustion, β2M knockout, and H-2Kb blockade evaluated immune dependence in vivo. RNA stability, RNA pulldown, RIP, co-immunoprecipitation, ubiquitination, and luciferase assays were conducted to define the molecular mechanisms.
RESULTS: NRGN was significantly upregulated in HCC and associated with advanced stage and poor survival, correlating inversely with GZMB⁺ CD8⁺ T cell infiltration. NRGN knockdown enriched MHC-I antigen presentation pathways and restored MHC-I/β2M expression, tumor cell surface antigen presentation, and CD8⁺ T cell cytotoxicity. In vivo, NRGN silencing suppressed tumor growth and prolonged survival in a CD8⁺ T cell-dependent manner, effects reversed by β2m deletion or H-2Kb blockade. Mechanistically, NRGN downregulated IRF8 by reducing its mRNA stability through FMR1 and stabilizing FMR1 protein via inhibition of MYCBP2-mediated ubiquitination, thereby sustaining suppression of antigen presentation.
CONCLUSIONS: NRGN suppresses antigen presentation via the FMR1-IRF8-MHC-I axis, thereby impairing CD8⁺ T cell-specific effector functions and promoting immune evasion in HCC. Modulation of the NRGN-IRF8-MHC-I axis could represent a potential strategy for improving immunotherapeutic responses.