Exosome-mediated genetic reprogramming of tumor-associated macrophages by exoASO-STAT6 leads to potent monotherapy antitumor activity.
Exosome-mediated genetic reprogramming of tumor-associated macrophages by exoASO-STAT6 leads to potent monotherapy antitumor activity.
复制标题
exoASO-STAT6 外泌体介导的肿瘤相关巨噬细胞基因重编程可产生有效的单一疗法抗肿瘤活性。
DOI：
10.1126/sciadv.abj7002
复制
发表时间：
2022-02-18
期刊：
影响因子：
13.6
通讯作者：
Sathyanarayanan S
中科院分区：
文献类型：
--
作者：
Kamerkar S;Leng C;Burenkova O;Jang SC;McCoy C;Zhang K;Dooley K;Kasera S;Zi T;Sisó S;Dahlberg W;Sia CL;Patel S;Schmidt K;Economides K;Soos T;Burzyn D;Sathyanarayanan S
具有M2表型的免疫抑制性肿瘤相关巨噬细胞（tam）可能会破坏检查点免疫治疗在癌症中的有效性。将tam重编程为促炎性M1表型是一种诱导抗肿瘤免疫的新方法。M2表型由关键转录因子控制，如信号换能器和转录激活因子6 (STAT6)，这些因子在tam中是“不可药物”选择性的。我们描述了一种工程化的治疗候选外泌体，其靶向STAT6 （exoASO-STAT6）的反义寡核苷酸（ASO），可选择性地沉默tam中STAT6的表达。在结直肠癌和肝细胞癌的同基因模型中，exoASO-STAT6单药治疗可抑制90%的肿瘤生长和50% - 80%的完全缓解。外源性aso - stat6可诱导M1巨噬细胞标志物一氧化氮合酶2 (NOS2)，导致肿瘤微环境重塑和CD8 T细胞介导的适应性免疫应答的产生。总的来说，exoASO-STAT6代表了第一个以高选择性方式靶向tam中转录因子的平台。ExoASO-STAT6是一种新的外泌体治疗药物，可选择性靶向肿瘤巨噬细胞，产生有效的抗肿瘤活性。
Effectiveness of checkpoint immunotherapy in cancer can be undermined by immunosuppressive tumor-associated macrophages (TAMs) with an M2 phenotype. Reprogramming TAMs toward a proinflammatory M1 phenotype is a novel approach to induce antitumor immunity. The M2 phenotype is controlled by key transcription factors such as signal transducer and activator of transcription 6 (STAT6), which have been “undruggable” selectively in TAMs. We describe an engineered exosome therapeutic candidate delivering an antisense oligonucleotide (ASO) targeting STAT6 (exoASO-STAT6), which selectively silences STAT6 expression in TAMs. In syngeneic models of colorectal cancer and hepatocellular carcinoma, exoASO-STAT6 monotherapy results in >90% tumor growth inhibition and 50 to 80% complete remissions. Administration of exoASO-STAT6 leads to induction of nitric oxide synthase 2 (NOS2), an M1 macrophage marker, resulting in remodeling of the tumor microenvironment and generation of a CD8 T cell–mediated adaptive immune response. Collectively, exoASO-STAT6 represents the first platform targeting transcription factors in TAMs in a highly selective manner. ExoASO-STAT6 is a novel exosome therapeutic that selectively targets tumor macrophages, resulting in potent antitumoral activity.
登录
查看更多内容
影响因子：
7.2
作者：
Holmgaard, Rikke B.;Brachfeld, Alexandra;Merghoub, Taha
通讯作者：
Merghoub, Taha
DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
影响因子：
32.4
作者：
Elo, Laura L.;Jarvenpaa, Henna;Lahesmaa, Riitta
通讯作者：
Lahesmaa, Riitta
高维分析描述了成功的免疫检查癌症治疗过程中髓样和淋巴室的重塑。
影响因子：
64.5
作者：
Gubin MM;Esaulova E;Ward JP;Malkova ON;Runci D;Wong P;Noguchi T;Arthur CD;Meng W;Alspach E;Medrano RFV;Fronick C;Fehlings M;Newell EW;Fulton RS;Sheehan KCF;Oh ST;Schreiber RD;Artyomov MN
通讯作者：
Artyomov MN
影响因子：
13.6
作者：
Guerriero JL
通讯作者：
Guerriero JL