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<p>Multiple myeloma (MM) is a clonal hematologic malignancy characterized by low rate of complete remissions. Cytokine-induced killer (CIK) cell therapy has shown promising benefits in MM treatment. In this study, we investigated whether the pro-inflammatory cytokines secreted by macrophages could upregulate MICA/B expression and thus the cytotoxicity of CIK cells. Flow cytometry was used for phenotypic measurement and the cytotoxicity assay of CIK cells. Soluble MICA/B and macrophage-derived cytokines were measured using ELISA assay. CCK-8 assay was applied to evaluate cell viabilities. Gene expression levels were investigated using RT-qPCR. The expression of MICA/B and PD-L1 in MM cells was upregulated by pro-inflammatory cytokines. Pro-inflammatory cytokines enhanced the cytotoxicity of CIK cells against MM cells, with TNF-α exhibiting a more potent effect than IL-1β and IL-6 as it strengthened both components of the NKG2D-MICA/B axis. PD-L1 blockade promoted the cytotoxic ability of CIK cells. Mechanistically, IL-1β, IL-6, and TNF-α enhanced the transcription of MICA/B and PD-L1 genes via the PI3K/AKT, JAK/STAT3, and MKK/p38 MAPK pathways. Pro-inflammatory cytokines upregulated the expression of MICA/B and PD-L1, thereby promoting the cytotoxicity of CIK cells against MM by strengthening the NKG2D pathway, while PD-L1 blockade enhanced the cytotoxicity of CIK cells.</p>

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Macrophage-derived pro-inflammatory cytokines augment the cytotoxicity of cytokine-induced killer cells by strengthening the NKG2D pathway in multiple myeloma

  • 期刊论文

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  • 发表日期：

    2025年5月14日

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  • Peng Chen,
  • Yinhao Chen,
  • Yulu Wang,
  • Amit Sharma,
  • Lukacs-Kornek Veronika,
  • Hans Weiher,
  • A. Gonzalez-Carmona Maria,
  • Ingo G. H. Schmidt-Wolf

摘要

Multiple myeloma (MM) is a clonal hematologic malignancy characterized by low rate of complete remissions. Cytokine-induced killer (CIK) cell therapy has shown promising benefits in MM treatment. In this study, we investigated whether the pro-inflammatory cytokines secreted by macrophages could upregulate MICA/B expression and thus the cytotoxicity of CIK cells. Flow cytometry was used for phenotypic measurement and the cytotoxicity assay of CIK cells. Soluble MICA/B and macrophage-derived cytokines were measured using ELISA assay. CCK-8 assay was applied to evaluate cell viabilities. Gene expression levels were investigated using RT-qPCR. The expression of MICA/B and PD-L1 in MM cells was upregulated by pro-inflammatory cytokines. Pro-inflammatory cytokines enhanced the cytotoxicity of CIK cells against MM cells, with TNF-α exhibiting a more potent effect than IL-1β and IL-6 as it strengthened both components of the NKG2D-MICA/B axis. PD-L1 blockade promoted the cytotoxic ability of CIK cells. Mechanistically, IL-1β, IL-6, and TNF-α enhanced the transcription of MICA/B and PD-L1 genes via the PI3K/AKT, JAK/STAT3, and MKK/p38 MAPK pathways. Pro-inflammatory cytokines upregulated the expression of MICA/B and PD-L1, thereby promoting the cytotoxicity of CIK cells against MM by strengthening the NKG2D pathway, while PD-L1 blockade enhanced the cytotoxicity of CIK cells.