MICA/B-targeted antibody promotes NK cell-driven tumor immunity in patients with intrahepatic cholangiocarcinoma.
MICA/B-targeted antibody promotes NK cell-driven tumor immunity in patients with intrahepatic cholangiocarcinoma.
复制标题
DOI：
10.1080/2162402x.2022.2035919
复制
发表时间：
2022
期刊：
影响因子：
7.2
通讯作者：
Mantovani S
中科院分区：
文献类型：
--
作者：
Oliviero B;Varchetta S;Mele D;Pessino G;Maiello R;Falleni M;Tosi D;Donadon M;Soldani C;Franceschini B;Torzilli G;Piccolo G;Barabino M;Opocher E;Maestri M;Bernuzzi S;Wucherpfennig KW;Mondelli MU;Mantovani S
主要的组织相容性复合体- I类链相关蛋白A和B （MICA/B）由于细胞应激而上调，而癌细胞的MICA/B脱落导致逃避NKG2D识别，有利于癌症的发生。胆管癌（CCA）是一种相对罕见，但越来越普遍的原发性肝癌，其特点是临床表现较晚，预后较差。我们研究了41例肝内胆管癌（iCCA）患者NK细胞的NKG2D-MICA/B轴。MICA/ b特异性7C6单抗用于体外抗体依赖性细胞毒性（ADCC）实验，使用循环，非肿瘤肝脏和肿瘤浸润NK细胞对HuCCT-1细胞系和患者来源的原代iCCA细胞作为靶点。MICA/B在iCCA中的表达高于非肿瘤组织，MICA转录在中度分化癌中高于低分化癌。iCCA患者血清MICA升高与ADAM10和ADAM17的高表达一致，ADAM10和ADAM17负责MICA/B从肿瘤中蛋白水解释放。添加7C6显著促进外周、肝脏和肿瘤浸润nk细胞脱颗粒和IFNγ对MICA/ b表达的已建立细胞系和自体iCCA患者靶细胞的产生。我们的数据显示，抗mica /B驱动NK细胞抗肿瘤活性，并提供临床前证据支持7C6作为iCCA的潜在免疫治疗工具。
The major histocompatibility complex-class I chain related proteins A and B (MICA/B) is upregulated because of cellular stress and MICA/B shedding by cancer cells causes escape from NKG2D recognition favoring the emergence of cancers. Cholangiocarcinoma (CCA) is a relatively rare, though increasingly prevalent, primary liver cancer characterized by a late clinical presentation and a dismal prognosis. We explored the NKG2D-MICA/B axis in NK cells from 41 patients with intrahepatic cholangiocarcinoma (iCCA). The MICA/B-specific 7C6 mAb was used for ex vivo antibody-dependent cytotoxicity (ADCC) experiments using circulating, non tumor liver- and tumor-infiltrating NK cells against the HuCCT-1 cell line and patient-derived primary iCCA cells as targets. MICA/B were more expressed in iCCA than in non-tumoral tissue, MICA transcription being higher in moderately-differentiated compared with poorly-differentiated cancer. Serum MICA was elevated in iCCA patients in line with higher expression of ADAM10 and ADAM17 that are responsible for proteolytic release of MICA/B from tumor. Addition of 7C6 significantly boosted peripheral, liver- and tumor-infiltrating-NK cell degranulation and IFNγ production toward MICA/B-expressing established cell lines and autologous iCCA patient target cells. Our data show that anti-MICA/B drives NK cell anti-tumor activity, and provide preclinical evidence in support of 7C6 as a potential immunotherapeutic tool for iCCA.