Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Department of Data Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.
Blood Cancer Discov. 2021 Sep;2(5):468-483. doi: 10.1158/2643-3230.BCD-21-0047. Epub 2021 Apr 23.
Proteasome inhibitor bortezomib induces apoptosis in multiple myeloma (MM) cells, and has transformed patient outcome. Using as well as immunodeficient and immunocompetent murine MM models, we here show that bortezomib also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a bortezomib-triggered specific ICD-gene signature associated with better outcome in two independent MM patient cohorts. Importantly, bortezomib stimulates MM cells immunogenicity activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate bortezomib-induced ICD. Our studies therefore delineate mechanisms whereby bortezomib exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in MM.
蛋白酶体抑制剂硼替佐米诱导多发性骨髓瘤（MM）细胞凋亡，并改变了患者的预后。我们利用 免疫缺陷和免疫功能正常的鼠 MM 模型，在此表明硼替佐米还可引发免疫原性细胞死亡（ICD），其特征是死亡的 MM 细胞暴露钙网蛋白、树突状细胞吞噬肿瘤细胞以及诱导 MM 特异性免疫。我们确定了硼替佐米触发的与两个独立的 MM 患者队列中更好的结果相关的特定 ICD 基因特征。重要的是，硼替佐米刺激 MM 细胞的免疫原性——激活 cGAS/STING 通路和产生 I 型干扰素；而 STING 激动剂显著增强了硼替佐米诱导的 ICD。因此，我们的研究阐明了硼替佐米发挥免疫治疗活性的机制，并为硼替佐米联合 STING 激动剂进行临床试验提供了框架，以诱导强烈的肿瘤特异性免疫并改善 MM 患者的预后。
