CD47xCD19 bispecific antibody triggers recruitment and activation of innate immune effector cells in a B-cell lymphoma xenograft model.
CD47xCD19 bispecific antibody triggers recruitment and activation of innate immune effector cells in a B-cell lymphoma xenograft model.
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DOI：
10.1186/s40164-022-00279-w
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发表时间：
2022-05-10
影响因子：
10.9
通讯作者：
Shang, Limin
中科院分区：
文献类型：
--
作者：
Chauchet, Xavier;Cons, Laura;Chatel, Laurence;Daubeuf, Bruno;Didelot, Gerard;Moine, Valery;Chollet, Didier;Malinge, Pauline;Pontini, Guillemette;Masternak, Krzysztof;Ferlin, Walter;Buatois, Vanessa;Shang, Limin
关键词：
CD 47/SIRPα轴被认为是先天性免疫检查点，新的临床数据证实了在癌症，特别是血液系统恶性肿瘤中阻断该途径的意义。在临床前模型中，CD 47/SIRPα阻断剂已显示可动员吞噬细胞并触发适应性免疫应答以消除肿瘤。在此，我们描述了CD 47 xCD 19双特异性抗体（NI-1701）在小鼠异种移植B细胞淋巴瘤模型中控制肿瘤生长的机制。使用流式细胞术、转录组学分析和体内免疫细胞耗竭实验研究NI-1701抗肿瘤活性背后的免疫效应细胞亚群的贡献。我们表明，NI-1701治疗将肿瘤微环境（TME）转化为更具抗肿瘤致瘤性的状态，NK细胞、单核细胞、树突状细胞（DC）和MHCIIhi肿瘤相关巨噬细胞（TAMs）增加，粒细胞骨髓源性抑制细胞减少。值得注意的是，NI-1701给药后分离的肿瘤浸润性白细胞的分子分析显示与免疫活化相关的基因上调，包括IFNγ和IL-12 b。此外，在NI-1701存在下，TME中TAM介导的淋巴瘤肿瘤细胞的吞噬作用增强，突出了巨噬细胞在肿瘤控制中的作用。体内细胞耗竭实验表明，巨噬细胞和NK细胞都有助于抗肿瘤活性。此外，NI-1701在体外增强树突状细胞介导的肿瘤细胞吞噬作用，导致肿瘤特异性CD 8 T细胞的交叉致敏增加。该研究描述了CD 47 xCD 19双特异性抗体NI-1701在淋巴瘤小鼠模型中控制肿瘤生长的机制。NI-1701目前正在I期临床试验中进行评估，用于治疗难治性或复发性B细胞淋巴瘤（NCT 04806035）。在线版本包含补充材料，可通过10.1186/s40164-022-00279-w获得。
CD47/SIRPα axis is recognized as an innate immune checkpoint and emerging clinical data validate the interest of interrupting this pathway in cancer, particularly in hematological malignancies. In preclinical models, CD47/SIRPα blocking agents have been shown to mobilize phagocytic cells and trigger adaptive immune responses to eliminate tumors. Here, we describe the mechanisms afforded by a CD47xCD19 bispecific antibody (NI-1701) at controlling tumor growth in a mouse xenograft B-cell lymphoma model. The contribution of immune effector cell subsets behind the antitumor activity of NI-1701 was investigated using flow cytometry, transcriptomic analysis, and in vivo immune-cell depletion experiments. We showed that NI-1701 treatment transformed the tumor microenvironment (TME) into a more anti-tumorigenic state with increased NK cells, monocytes, dendritic cells (DC) and MHCIIhi tumor-associated macrophages (TAMs) and decreased granulocytic myeloid-derived suppressor cells. Notably, molecular analysis of isolated tumor-infiltrating leukocytes following NI-1701 administration revealed an upregulation of genes linked to immune activation, including IFNγ and IL-12b. Moreover, TAM-mediated phagocytosis of lymphoma tumor cells was enhanced in the TME in the presence of NI-1701, highlighting the role of macrophages in tumor control. In vivo cell depletion experiments demonstrated that both macrophages and NK cells contribute to the antitumor activity. In addition, NI-1701 enhanced dendritic cell-mediated phagocytosis of tumor cells in vitro, resulting in an increased cross-priming of tumor-specific CD8 T cells. The study described the mechanisms afforded by the CD47xCD19 bispecific antibody, NI-1701, at controlling tumor growth in lymphoma mouse model. NI-1701 is currently being evaluated in a Phase I clinical trial for the treatment of refractory or relapsed B-cell lymphoma (NCT04806035). The online version contains supplementary material available at 10.1186/s40164-022-00279-w.
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影响因子：
7.2
作者：
Hendriks MAJM;Ploeg EM;Koopmans I;Britsch I;Ke X;Samplonius DF;Helfrich W
通讯作者：
Helfrich W
DOI：
10.1161/atvbaha.117.310607
发表时间：
2018-03
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Chang CL;Garcia-Arcos I;Nyrén R;Olivecrona G;Kim JY;Hu Y;Agrawal RR;Murphy AJ;Goldberg IJ;Deckelbaum RJ
通讯作者：
Deckelbaum RJ
影响因子：
64.8
作者：
Guerriero JL;Sotayo A;Ponichtera HE;Castrillon JA;Pourzia AL;Schad S;Johnson SF;Carrasco RD;Lazo S;Bronson RT;Davis SP;Lobera M;Nolan MA;Letai A
通讯作者：
Letai A
DOI：
10.1073/pnas.1721434116
发表时间：
2019-01-15
影响因子：
11.1
作者：
Hutter, Gregor;Theruvath, Johanna;Cheshier, Samuel H.
通讯作者：
Cheshier, Samuel H.
影响因子：
10.9
作者：
Cannarile MA;Weisser M;Jacob W;Jegg AM;Ries CH;Rüttinger D
通讯作者：
Rüttinger D