RESUMEN
Exosomal long noncoding RNAs (lncRNA) derived from cancer cells are implicated in various processes, including cancer cell proliferation, metastasis, and immunomodulation. We investigated the role and underlying mechanism of exosome-transmitted lncRNA NEAT1 in the immune escape of multiple myeloma cells from natural killer (NK) cells. Multiple myeloma cells and samples from patients with multiple myeloma were obtained. The effects of multiple myeloma cell-derived exosomes (multiple myeloma exosomes) and exosomal NEAT1 on the functions of NK cells were evaluated using EdU staining, CCK-8, flow cytometry, and ELISA. Chromatin and RNA immunoprecipitation were performed to identify interactions between NEAT1, enhancer of Zeste Homolog 2 (EZH2), and pre-B-cell leukemia transcription factor 1 (PBX1). A xenograft tumor model was constructed to verify the effects of exosomal NEAT1 on tumor growth. qRT-PCR, Western blot analysis, and IHC were conducted to detect related genes. NEAT1 levels were upregulated in multiple myeloma tumor tissues, multiple myeloma cells, and multiple myeloma exosomes. Multiple myeloma exosomes suppressed cell proliferation, promoted apoptosis, reduced natural killer group 2, member D (NKG2D)-positive cells, and the production of TNFα) and interferon-gamma (IFN-γ) in NK cells, whereas NEAT1-silenced exosomes had little effect. NEAT1 silenced PBX1 by recruiting EZH2. PBX1 knockdown abrogated the effects of NEAT1-silenced exosomes on NK and multiple myeloma cells. NEAT1-silenced exosomes inhibited tumor growth in mice, decreased Ki67 and PD-L1, and increased NKG2D, TNFα, and IFNγ in tumor tissues. In summary, multiple myeloma cell-derived exosomal NEAT1 suppressed NK-cell activity by downregulating PBX1, promoting multiple myeloma cell immune escape. This study suggests a potential strategy for treating multiple myeloma. IMPLICATIONS: This study reveals that exosomal NEAT1 regulates EZH2/PBX1 axis to inhibit NK-cell activity, thereby promoting multiple myeloma cell immune escape, which offers a novel therapeutic potential for multiple myeloma.
Asunto(s)
Exosomas , MicroARNs , Mieloma Múltiple , ARN Largo no Codificante , Animales , Humanos , Ratones , Línea Celular Tumoral , Proliferación Celular , Proteína Potenciadora del Homólogo Zeste 2/genética , Exosomas/genética , Células Asesinas Naturales , MicroARNs/genética , Mieloma Múltiple/genética , Subfamilia K de Receptores Similares a Lectina de Células NK , Factor de Transcripción 1 de la Leucemia de Células Pre-B , ARN Largo no Codificante/genética , Factor de Necrosis Tumoral alfaRESUMEN
RATIONALE: Significant concerns about the adverse effects following chimeric antigen receptor T cell (CAR-T) therapy are still remained including cytokine release syndrome (CRS). In rare circumstances, CRS may be refractory to tocilizumab and/or corticosteroids, a new treatment is needed for the management of CRS. PATIENT CONCERNS: We present a case of a 20-year-old male patient with acute lymphoblastic leukemia developed CRS after CD19/CD22 bispecific CAR-T treatment. DIAGNOSIS: The patient was diagnosed with BCR-ABL(P210) positive B-ALL and developed CRS after CD19/CD22 bispecific CAR-T treatment. INTERVENTIONS: Tocilizumab and methylprednisolone were administered, unfortunately the patient's symptoms of CRS were still not resolved. Another methylprednisolone and ruxolitinib were administered. OUTCOMES: The persistent fever and hypotension of this patient achieved a rapid clinical remission within hours after ruxolitinib administration. LESSONS: Ruxolitinib can be used as an alternative therapeutic approach for severe and refractory CRS without impairing CAR-T amplification and anti-tumor effect.
