肿瘤细胞治疗研究
英文原题：Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma.
这些发现表明KDM6A缺失是Daratumumab耐药的一种机制，并为EZH2抑制剂（其中一种已获FDA批准）在提高MM对Daratumumab反应性方面的治疗应用奠定了原理验证基础。
抗CD38单克隆抗体如Daratumumab（Dara）在多发性骨髓瘤（MM）中有效；然而，耐药最终会发生，其背后的机制尚不清楚。在此，我们通过两个体外全基因组CRISPR筛选探究Daratumumab耐药性，确定KDM6A是Daratumumab介导的抗体依赖性细胞毒性（ADCC）敏感性的重要调节因子。KDM6A缺失导致CD38启动子上H3K27me3水平升高，导致CD38表达显著下调，这可能引起对Daratumumab介导的ADCC的耐药。重新引入CD38并不能完全逆转Daratumumab介导的ADCC，这表明其他KDM6A靶点，包括在KDM6A缺失时也下调的CD48，也参与Daratumumab介导的ADCC。用EZH2抑制剂抑制H3K27me3导致CD38和CD48上调，并恢复对Daratumumab的敏感性。这些发现表明KDM6A缺失是Daratumumab耐药的一种机制，并为EZH2抑制剂的治疗应用奠定了原理证明，其中一种已获FDA批准，用于改善MM对Daratumumab的反应性。
Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC. Re-introducing CD38 does not reverse Daratumumab-mediated ADCC fully, which suggests that additional KDM6A targets, including CD48 which is also downregulated upon KDM6A loss, contribute to Daratumumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2 inhibitor resulted in CD38 and CD48 upregulation and restored sensitivity to Daratumumab. These findings suggest KDM6A loss as a mechanism of Daratumumab resistance and lay down the proof of principle for the therapeutic application of EZH2 inhibitors, one of which is already FDA-approved, in improving MM responsiveness to Daratumumab.
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