平原 潔

ABSTRACT While antibody‐dependent cellular cytotoxicity (ADCC) by anti‐disialoganglioside GD2 monoclonal antibody (mAb) has succeeded in increasing the survival rate of high‐risk patients with neuroblastoma, approximately 40%–50% of patients die from the disease. Recently, we developed induced pluripotent stem cell‐derived natural killer T (iPS‐NKT) cells, which exhibit NK‐like cytotoxicity. However, whether iPS‐NKT cells can induce ADCC function is unclear. Here, we investigated the ADCC of iPS‐NKT cells and the efficacy of the combination treatment of anti‐GD2 mAb and iPS‐NKT cells against neuroblastoma. Anti‐GD2 mAb enhanced the cytotoxicity and secretion of cytokines and cytotoxic granules of iPS‐NKT cells, which expressed CD16 to GD2‐expressing neuroblastoma cell lines. We also examined which Fcγ receptors contribute to ADCC of iPS‐NKT cells. CD16 stimulation against iPS‐NKT cells caused cytotoxicity and secretion of interferon‐gamma, tumor necrosis factor, and granzyme B. In contrast, CD32 and CD64 stimulation did not. In vivo, the intratumor administration of anti‐GD2 mAb and iPS‐NKT cells significantly inhibited tumor growth compared with the other treatment groups: no treatment, anti‐GD2 mAb alone, and iPS‐NKT cells alone. In conclusion, iPS‐NKT cells exhibit CD16‐mediated ADCC, and the addition of iPS‐NKT cells to anti‐GD2 mAb therapy may be a potential approach for immunotherapy against neuroblastoma.

Abstract Purpose Auto-antibodies (auto-abs) to type I interferons (IFNs) have been identified in patients with life-threatening coronavirus disease 2019 (COVID-19), suggesting that the presence of auto-abs may be a risk factor for disease severity. We therefore investigated the mechanism underlying COVID-19 exacerbation induced by auto-abs to type I IFNs. Methods We evaluated plasma from 123 patients with COVID-19 to measure auto-abs to type I IFNs. We performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells from the patients with auto-abs and conducted epitope mapping of the auto-abs. Results Three of 19 severe and 4 of 42 critical COVID-19 patients had neutralizing auto-abs to type I IFNs. Patients with auto-abs to type I IFNs showed no characteristic clinical features. scRNA-seq from 38 patients with COVID-19 revealed that IFN signaling in conventional dendritic cells and canonical monocytes was attenuated, and SARS-CoV-2-specific BCR repertoires were decreased in patients with auto-abs. Furthermore, auto-abs to IFN-α2 from COVID-19 patients with auto-abs recognized characteristic epitopes of IFN-α2, which binds to the receptor. Conclusion Auto-abs to type I IFN found in COVID-19 patients inhibited IFN signaling in dendritic cells and monocytes by blocking the binding of type I IFN to its receptor. The failure to properly induce production of an antibody to SARS-CoV-2 may be a causative factor of COVID-19 severity.