Human chimeric antigen receptor macrophages for cancer immunotherapy.
Human chimeric antigen receptor macrophages for cancer immunotherapy.
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DOI：
10.1038/s41587-020-0462-y
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发表时间：
2020-08
影响因子：
46.9
通讯作者：
Gill S
中科院分区：
文献类型：
--
作者：
Klichinsky M;Ruella M;Shestova O;Lu XM;Best A;Zeeman M;Schmierer M;Gabrusiewicz K;Anderson NR;Petty NE;Cummins KD;Shen F;Shan X;Veliz K;Blouch K;Yashiro-Ohtani Y;Kenderian SS;Kim MY;O'Connor RS;Wallace SR;Kozlowski MS;Marchione DM;Shestov M;Garcia BA;June CH;Gill S
嵌合抗原受体（CAR）T细胞疗法在血液恶性肿瘤中显示出前景，但其在实体瘤中的应用一直具有挑战性。鉴于巨噬细胞独特的效应子功能及其穿透肿瘤的能力，我们用汽车基因工程改造了人巨噬细胞，以指导其对肿瘤的吞噬活性。我们发现嵌合腺病毒载体克服了原代人巨噬细胞对遗传操作的固有抗性，并赋予了持续的促炎（M1）表型。CAR巨噬细胞（CAR-Ms）在体外表现出抗原特异性吞噬作用和肿瘤清除作用。在两种实体瘤异种移植小鼠模型中，单次输注人CAR-M降低了肿瘤负荷并延长了总生存期。CAR-M活性的表征表明，CAR-M表达促炎细胞因子和趋化因子，将旁观者M2巨噬细胞转化为M1，上调抗原呈递机制，招募并将抗原呈递给T细胞，并抵抗免疫抑制细胞因子的作用。在人源化小鼠模型中，CAR-M进一步显示出诱导促炎性肿瘤微环境并增强抗肿瘤T细胞活性。
Chimeric antigen receptor (CAR) T cell therapy has shown promise in hematologic malignancies, but its application to solid tumors has been challenging. Given the unique effector functions of macrophages and their capacity to penetrate tumors, we genetically engineered human macrophages with CARs to direct their phagocytic activity against tumors. We found that a chimeric adenoviral vector overcame the inherent resistance of primary human macrophages to genetic manipulation and imparted a sustained pro-inflammatory (M1) phenotype. CAR macrophages (CAR-Ms) demonstrated antigen-specific phagocytosis and tumor clearance in vitro. In two solid tumor xenograft mouse models, a single infusion of human CAR-Ms decreased tumor burden and prolonged overall survival. Characterization of CAR-M activity showed that CAR-Ms expressed pro-inflammatory cytokines and chemokines, converted bystander M2 macrophages to M1, upregulated antigen presentation machinery, recruited and presented antigen to T cells and resisted the effects of immunosuppressive cytokines. In humanized mouse models, CAR-Ms were further shown to induce a pro-inflammatory tumor microenvironment and boost anti-tumor T cell activity.
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影响因子：
82.9
作者：
Gaggar, A;Shayakhmetov, DM;Lieber, A
通讯作者：
Lieber, A
影响因子：
5.1
作者：
Bobadilla, S.;Sunseri, N.;Landau, N. R.
通讯作者：
Landau, N. R.
影响因子：
44.1
作者：
通讯作者：
--
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
3.5
作者：
Nilsson, M;Ljungberg, J;Fan, XL
通讯作者：
Fan, XL