The IRE1α Endonuclease Plays a Dual Role in Regulating the XBP1/miRNA-34a Axis and PD-1 Expression within Natural Killer Cells in Hodgkin Lymphoma

Introduction: Hodgkin lymphoma (HL) is deficient in major histocompatibility complex class I, rendering it susceptible to antitumoral immunity by natural killer (NK) cells. Despite the functional impairment of PD-1⁺ NK cells in HL, the underlying mechanisms of NK cell dysfunction remain unclear. Methods: This study involved 14 HL patients and SNK10/KHYG-1 cell lines to assess NK cell activation against cancer cells. Activation was measured through transcript (PCR) and protein expression (flow cytometry). Regulatory mechanisms associated with IRE1α activation were validated through knockdown and luciferase reporter assays. Results: Our findings reveal a novel role for IRE1α-endonuclease in fine-tuning NK cell effector functions by orchestrating the XBP1s/microRNA-34a-5p/PD-1 axis. When NK cells encounter cancer cells, IRE1α endonuclease activates the decay of microRNA-34a-5p, resulting in increased expression of XBP1s and PD-1. IRE1α-endonuclease activation enhances NK cell functions while promoting PD-1 expression. In turn, PD-1 is directly regulated by microRNA-34a-5p, which binds to the 3′UTR of PD-1 transcript to repress PD-1 protein on the NK cell surface. Importantly, IRE1α-pathway activation is impaired in NK cells from HL patients. Conclusion: The IRE1α endonuclease emerges as a key player, simultaneously regulating the XBP1s/microRNA-34a-5p/PD-1 axis in NK cells, a process disrupted in HL. Targeting the IRE1α-pathway holds promise as a therapeutic strategy to optimize NK cell functions in Hodgkin lymphoma treatments.