CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells.
CXCR5 CAR-T cells simultaneously target B cell non-Hodgkin's lymphoma and tumor-supportive follicular T helper cells.
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DOI：
10.1038/s41467-020-20488-3
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发表时间：
2021-01-11
影响因子：
16.6
通讯作者：
Höpken UE
中科院分区：
文献类型：
--
作者：
Bunse M;Pfeilschifter J;Bluhm J;Zschummel M;Joedicke JJ;Wirges A;Stark H;Kretschmer V;Chmielewski M;Uckert W;Abken H;Westermann J;Rehm A;Höpken UE
靶向CD 19的CAR-T细胞疗法对晚期B细胞白血病表现出较强的活性，但对淋巴结播散的淋巴瘤表现出较低的疗效。为了靶向肿瘤微环境（TME）中的B细胞非霍奇金淋巴瘤（B-NHL）和滤泡性T辅助（Tfh）细胞，我们在此应用以高亲合力识别人CXCR 5的嵌合抗原受体（CAR）。在成熟B和Tfh细胞上生理性表达的CXCR 5也在结B-NHL上高度表达。抗CXCR 5 CAR-T细胞在体外比CD 19 CAR-T细胞更有效地根除B-NHL细胞和淋巴瘤支持性Tfh细胞，并且它们在小鼠异种移植模型中有效地抑制淋巴瘤生长。在同系小鼠中给予抗鼠CXCR 5 CAR-T细胞可特异性耗竭内源性和恶性B和Tfh细胞，而无非预期的靶向/脱瘤效应。总的来说，抗CXCR 5 CAR-T细胞通过同时消除支持肿瘤的TME的淋巴瘤B细胞和Tfh细胞，为结B-NHL提供了一种有希望的治疗策略。靶向CD 19的CAR-T细胞疗法治疗淋巴结播散的淋巴瘤不如治疗B细胞白血病有效。在这里，作者产生了针对CXCR 5的CAR-T细胞，并显示它们通过耗尽淋巴瘤模型中的B和滤泡T辅助细胞来抑制肿瘤生长。
CAR-T cell therapy targeting CD19 demonstrated strong activity against advanced B cell leukemia, however shows less efficacy against lymphoma with nodal dissemination. To target both B cell Non-Hodgkin’s lymphoma (B-NHLs) and follicular T helper (Tfh) cells in the tumor microenvironment (TME), we apply here a chimeric antigen receptor (CAR) that recognizes human CXCR5 with high avidity. CXCR5, physiologically expressed on mature B and Tfh cells, is also highly expressed on nodal B-NHLs. Anti-CXCR5 CAR-T cells eradicate B-NHL cells and lymphoma-supportive Tfh cells more potently than CD19 CAR-T cells in vitro, and they efficiently inhibit lymphoma growth in a murine xenograft model. Administration of anti-murine CXCR5 CAR-T cells in syngeneic mice specifically depletes endogenous and malignant B and Tfh cells without unexpected on-target/off-tumor effects. Collectively, anti-CXCR5 CAR-T cells provide a promising treatment strategy for nodal B-NHLs through the simultaneous elimination of lymphoma B cells and Tfh cells of the tumor-supporting TME. CAR-T cell therapy targeting CD19 is not as efficient to treat lymphoma with nodal dissemination as it is for B cell leukaemia. Here, the authors generate CAR-T cells against CXCR5 and show they inhibit tumour growth by depleting both B and follicular T helper cells in lymphoma models.
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影响因子：
11.4
作者：
Hipp, S.;Tai, Y-T;Friedrich, M.
通讯作者：
Friedrich, M.
影响因子：
6.5
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影响因子：
20.3
作者：
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Abken, Hinrich
影响因子：
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作者：
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Hoepken, Uta E.
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作者：
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