HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells.
HER2-targeted antibody-drug conjugate induces host immunity against cancer stem cells.
复制标题
DOI：
10.1016/j.chembiol.2021.02.013
复制
发表时间：
2021-05-20
影响因子：
8.6
通讯作者：
Li Q
中科院分区：
文献类型：
--
作者：
Xia L;Wen L;Qin Y;Dobson HE;Zhang T;Comer FI;Hinrichs MJ;Oberst MD;Coats SR;Chang AE;Liu Y;Bao Y;Dai F;Wicha MS;Li Q
我们之前在免疫功能低下（SCID）小鼠中测试了HER 2靶向抗体药物偶联物（ADC），排除了对宿主免疫力、对癌症干细胞（CSC）的影响以及与PD-L1阻断剂联合使用时的潜在获益的评价。在本研究中，我们在两种免疫活性小鼠肿瘤模型中测试了HER 2靶向ADC。HER 2靶向ADC特异性抑制HER 2表达肿瘤的生长，延长动物生存期，并减少HER 2+和PD-L1+细胞。ADC+抗PD-L1抗体增强了治疗效果，调节了免疫基因特征，增加了CD 3+和CD 19+肿瘤浸润淋巴细胞（TIL）的数量和功能，诱导了肿瘤抗原特异性免疫记忆，刺激了全身和肿瘤微环境中的B细胞活化、分化和IgG 1产生。此外，ADC治疗调节TIL中的T细胞亚群及其活化。此外，HER 2靶向ADC降低了ALDHhi CSC的数量和致瘤性。该研究表明，HER 2靶向ADC有效靶向ALDHhi CSC，并且这种作用通过共施用抗PD-L1抗体而增强。当前癌症管理的一个主要挑战是由于CSC对传统疗法具有抗性而导致的疾病复发。在这里，Xia及其同事表明，HER 2靶向ADC通过诱导抗肿瘤细胞和体液免疫应答以及免疫记忆靶向大块肿瘤细胞和ALDHhigh CSC。
We previously tested HER2-targeted antibody drug conjugates (ADC) in immunocompromised (SCID) mice, precluding evaluation of host immunity, impact on cancer stem cells (CSCs), and potential benefit when combined with PD-L1 blockade. In this study, we tested HER2-targeted ADC in two immunocompetent mouse tumor models. HER2-targeted ADC specifically inhibited the growth of HER2-expressing tumors, prolonged animal survival, and reduced HER2+ and PD-L1+ cells. ADC plus anti-PD-L1 antibody augmented therapeutic efficacy, modulated immune gene signatures, increased the number and function of CD3+ and CD19+ tumor-infiltrating lymphocytes (TILs), induced tumor antigen specific immunological memory, stimulated B cell activation, differentiation, and IgG1 production both systemically and in the tumor microenvironment. In addition, ADC therapy modulated T cell subsets and their activation in TILs. Furthermore, HER2-targeted ADC reduced the number and tumorigenicity of ALDHhi CSCs. This study demonstrates that HER2-targeted ADC effectively targets ALDHhi CSCs and this effect is augmented by co-administration of anti-PD-L1 antibody. A major challenge for current cancer management is the relapse of the disease due to CSCs that are resistant to traditional therapies. Here, Xia and colleagues show that HER2-targeted ADC targets both bulk tumor cells and ALDHhigh CSCs via inducing anti-tumor cellular and humoral immune responses and immunological memory.
登录
查看更多内容
影响因子：
3.8
作者：
Li Y;Opyrchal M;Yao S;Peng X;Yan L;Jabbour H;Khoury T
通讯作者：
Khoury T
影响因子：
10.9
作者：
D'Amico, Lucia;Menzel, Ulrike;Zippelius, Alfred
通讯作者：
Zippelius, Alfred
影响因子：
11.4
作者：
Cheung, A. M. S.;Wan, T. S. K.;Leung, A. Y. H.
通讯作者：
Leung, A. Y. H.
影响因子：
3.7
作者：
Deng S;Yang X;Lassus H;Liang S;Kaur S;Ye Q;Li C;Wang LP;Roby KF;Orsulic S;Connolly DC;Zhang Y;Montone K;Bützow R;Coukos G;Zhang L
通讯作者：
Zhang L
影响因子：
11.2
作者：
Ithimakin S;Day KC;Malik F;Zen Q;Dawsey SJ;Bersano-Begey TF;Quraishi AA;Ignatoski KW;Daignault S;Davis A;Hall CL;Palanisamy N;Heath AN;Tawakkol N;Luther TK;Clouthier SG;Chadwick WA;Day ML;Kleer CG;Thomas DG;Hayes DF;Korkaya H;Wicha MS
通讯作者：
Wicha MS