Abstract：
The immune system has a strong connection to tumors. When a tumor cell is recognized as an abnormal cell by the immune system, the immune system may initiate an immune response to kill the tumor cell. In this study, RNA sequencing was performed on multiple myeloma (MM) cells treated with the proteasome inhibitor FHND6091. The transcriptional changes induced by FHND6091 in RPMI8226 cells aligned notably with immune response activation and results indicated upregulation of cGAS-STING pathway-related genes in the FHND6091-treated group. In vivo and in vitro experiments had demonstrated that FHND6091 stimulated the immunoreaction of MM cells via activation of the cyclic guanosine monophosphate-adenosine synthase/stimulator of interferon genes (cGAS-STING) pathway. This activation resulted in the generation of type-I interferons and the mobilization of natural killer (NK) cells. Notably, FHND6091 upregulated the levels of calreticulin and the protein ligands UL16-binding protein 2/5/6, MHC class I chain-related A (MICA), and MICB on the surface of MM cells. Subsequently, upon engaging with the surface activation receptors of NK cells, these ligands triggered NK cell activation, leading to the subsequent elimination of tumor cells. Thus, our findings elucidated the mechanism whereby FHND6091 exerted its immunotherapeutic activity as a STING agonist, enhancing the killing ability of NK cells against tumor cells.
摘要：
免疫系统与肿瘤有很强的联系。当肿瘤细胞被免疫系统识别为异常细胞时，免疫系统可以启动免疫反应以杀死肿瘤细胞。在这项研究中,在用蛋白酶体抑制剂FHND6091处理的多发性骨髓瘤(MM)细胞上进行RNA测序。在RPMI8226细胞中由FHND6091诱导的转录变化与免疫应答激活显著一致,并且结果表明在FHND6091处理组中cGAS-STING途径相关基因上调。体内和体外实验表明，FHND6091通过激活环磷酸鸟苷-腺苷合酶/干扰素基因刺激物（cGAS-STING）途径刺激MM细胞的免疫反应。这种激活导致I型干扰素的产生和自然杀伤（NK）细胞的动员。值得注意的是,FHND6091上调钙网蛋白和蛋白质配体UL16结合蛋白2/5/6，MHCI类链相关A（MICA）的水平，和MICB在MM细胞表面。随后，与NK细胞的表面活化受体接触后，这些配体触发了NK细胞活化，导致随后的肿瘤细胞的消除。因此，我们的发现阐明了FHND6091发挥其作为STING激动剂的免疫治疗活性的机制，增强NK细胞对肿瘤细胞的杀伤能力。
