GPC2 antibody-drug conjugate reprograms the neuroblastoma immune milieu to enhance macrophage-driven therapies.
GPC2 antibody-drug conjugate reprograms the neuroblastoma immune milieu to enhance macrophage-driven therapies.
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GPC 2抗体-药物偶联物重编程神经母细胞瘤免疫环境以增强巨噬细胞驱动的疗法
DOI：
10.1136/jitc-2022-004704
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发表时间：
2022-12
影响因子：
10.9
通讯作者：
中科院分区：
文献类型：
--
作者：
向肿瘤细胞递送细胞毒性药物的抗体药物偶联物（ADC）已成为一种有效且安全的抗癌疗法。 ADC 可能会诱导免疫原性细胞死亡 (ICD)，以促进额外的内源性抗肿瘤免疫反应。在这里，我们表征了 D3-GPC2-PBD 的免疫调节特性，D3-GPC2-PBD 是一种吡咯并苯二氮卓 (PBD) 二聚体 ADC，靶向磷脂酰肌醇蛋白聚糖 2 (GPC2)，一种在神经母细胞瘤中高度差异表达的细胞表面癌蛋白。在表达 GPC2 的小鼠神经母细胞瘤中体外和体内研究了 ADC 介导的 ICD 诱导。通过 RNA 测序、细胞因子阵列、飞行时间细胞计数和流式细胞术来分析神经母细胞瘤肿瘤微环境的 ADC 重编程。在神经母细胞瘤同种异体移植物和人类患者来源的异种移植物中测试了 ADC 与巨噬细胞驱动的免疫调节剂结合的功效。 D3-GPC2-PBD ADC 诱导 ICD 生物标志物，包括钙网蛋白和热休克蛋白 (HSP70/90) 的神经母细胞瘤细胞膜易位以及高迁移率族盒 1 和 ATP 的释放。用 ADC 处理的小鼠神经母细胞瘤细胞对具有免疫活性的小鼠进行疫苗接种，可促进 T 细胞介导的免疫反应，从而保护动物免受肿瘤的再次攻击。在这些同基因神经母细胞瘤模型中，ADC 治疗还将肿瘤免疫微环境重新编程为促炎状态，同时激活的巨噬细胞和 T 细胞的肿瘤运输增加。反过来，巨噬细胞或 T 细胞抑制会损害 ADC 体内功效，而 CD40 激动剂和 CD47 拮抗剂抗体会交替增强 ADC 功效。在人神经母细胞瘤中，D3-GPC2-PBD ADC 还诱导 ICD 并促进巨噬细胞的肿瘤吞噬作用，当体外和体内阻断 CD47 信号传导时，这种吞噬作用进一步增强。我们阐明了 GPC2 靶向 ADC 的免疫调节特性，并在多种神经母细胞瘤临床前模型中显示了联合免疫疗法的强大功效。
Antibody–drug conjugates (ADCs) that deliver cytotoxic drugs to tumor cells have emerged as an effective and safe anticancer therapy. ADCs may induce immunogenic cell death (ICD) to promote additional endogenous antitumor immune responses. Here, we characterized the immunomodulatory properties of D3-GPC2-PBD, a pyrrolobenzodiazepine (PBD) dimer-bearing ADC that targets glypican 2 (GPC2), a cell surface oncoprotein highly differentially expressed in neuroblastoma. ADC-mediated induction of ICD was studied in GPC2-expressing murine neuroblastomas in vitro and in vivo. ADC reprogramming of the neuroblastoma tumor microenvironment was profiled by RNA sequencing, cytokine arrays, cytometry by time of flight and flow cytometry. ADC efficacy was tested in combination with macrophage-driven immunoregulators in neuroblastoma syngeneic allografts and human patient-derived xenografts. The D3-GPC2-PBD ADC induced biomarkers of ICD, including neuroblastoma cell membrane translocation of calreticulin and heat shock proteins (HSP70/90) and release of high-mobility group box 1 and ATP. Vaccination of immunocompetent mice with ADC-treated murine neuroblastoma cells promoted T cell-mediated immune responses that protected animals against tumor rechallenge. ADC treatment also reprogrammed the tumor immune microenvironment to a proinflammatory state in these syngeneic neuroblastoma models, with increased tumor trafficking of activated macrophages and T cells. In turn, macrophage or T-cell inhibition impaired ADC efficacy in vivo, which was alternatively enhanced by both CD40 agonist and CD47 antagonist antibodies. In human neuroblastomas, the D3-GPC2-PBD ADC also induced ICD and promoted tumor phagocytosis by macrophages, which was further enhanced when blocking CD47 signaling in vitro and in vivo. We elucidated the immunoregulatory properties of a GPC2-targeted ADC and showed robust efficacy of combination immunotherapies in diverse neuroblastoma preclinical models.
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影响因子：
5.7
作者：
通讯作者：
--
DOI：
10.1084/jem.20050915
发表时间：
2005-12-19
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casares N;Pequignot MO;Tesniere A;Ghiringhelli F;Roux S;Chaput N;Schmitt E;Hamai A;Hervas-Stubbs S;Obeid M;Coutant F;Métivier D;Pichard E;Aucouturier P;Pierron G;Garrido C;Zitvogel L;Kroemer G
通讯作者：
Kroemer G
影响因子：
10.9
作者：
D'Amico, Lucia;Menzel, Ulrike;Zippelius, Alfred
通讯作者：
Zippelius, Alfred
DOI：
10.1073/pnas.2010197117
发表时间：
2020-11-24
影响因子：
11.1
作者：
Li W;Chen C;Drelich A;Martinez DR;Gralinski LE;Sun Z;Schäfer A;Kulkarni SS;Liu X;Leist SR;Zhelev DV;Zhang L;Kim YJ;Peterson EC;Conard A;Mellors JW;Tseng CK;Falzarano D;Baric RS;Dimitrov DS
通讯作者：
Dimitrov DS
影响因子：
3.8
作者：
Kee JY;Ito A;Hojo S;Hashimoto I;Igarashi Y;Tsuneyama K;Tsukada K;Irimura T;Shibahara N;Takasaki I;Inujima A;Nakayama T;Yoshie O;Sakurai H;Saiki I;Koizumi K
通讯作者：
Koizumi K