Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma.
Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma.
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DOI：
10.1186/s40425-017-0275-9
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发表时间：
2017-09-19
影响因子：
10.9
通讯作者：
Lundqvist A
中科院分区：
文献类型：
--
作者：
Kremer V;Ligtenberg MA;Zendehdel R;Seitz C;Duivenvoorden A;Wennerberg E;Colón E;Scherman-Plogell AH;Lundqvist A
连续性自然杀伤（NK）细胞转移越来越多地用于癌症治疗。然而，迄今为止，临床反应仅限于血液恶性肿瘤患者。实体瘤患者的一个潜在限制因素是输注的NK细胞向肿瘤部位的归巢缺陷。趋化因子调节表达相应趋化因子受体的白细胞的迁移。各种实体瘤，包括肾细胞癌（RCC），容易分泌趋化因子受体CXCR 2的配体。我们假设输注表达高水平CXCR 2趋化因子受体的NK细胞将导致转移的NK细胞流入肿瘤的增加，并改善癌症患者的临床结局。通过流式细胞术和趋化因子分析对14例原发性RCC患者的血液和肿瘤活检进行了评估。使用逆转录病毒系统用人CXCR 2转导原代NK细胞。通过钙通量测定CXCR 2受体功能，并在transwell测定中评价NK细胞迁移。我们检测到较高浓度的CXCR 2配体在肿瘤与RCC患者的血浆相比。此外，CXCL 5水平与CXCR 2阳性NK细胞的肿瘤内浸润相关。然而，与外周血NK细胞相比，来自RCC患者的肿瘤浸润NK细胞表达较低的CXCR 2。此外，健康供体NK细胞在体外培养和扩增后迅速丧失其CXCR 2表达。与对照相比，对人原代NK细胞进行基因修饰以重新表达CXCR 2提高了它们沿着重组CXCR 2配体或RCC肿瘤上清液的趋化因子梯度特异性迁移的能力。增强的贩运导致靶细胞的杀伤增加。此外，虽然与对照NK细胞相比，它们的功能保持不变，但CXCR 2转导的NK细胞获得了增加的粘附特性，并与靶细胞形成了更多的缀合物。为了提高基于NK细胞的实体瘤治疗的成功率，促进它们归巢到肿瘤部位是非常重要的。在这项研究中，我们表明，稳定工程的人原代NK细胞表达趋化因子受体，从而提高其迁移是一个有前途的策略，以提高抗肿瘤反应后过继转移的NK细胞。本文的在线版本（doi：10.1186/s40425-017-0275-9）包含补充材料，可供授权用户使用。
Adoptive natural killer (NK) cell transfer is being increasingly used as cancer treatment. However, clinical responses have so far been limited to patients with hematological malignancies. A potential limiting factor in patients with solid tumors is defective homing of the infused NK cells to the tumor site. Chemokines regulate the migration of leukocytes expressing corresponding chemokine receptors. Various solid tumors, including renal cell carcinoma (RCC), readily secrete ligands for the chemokine receptor CXCR2. We hypothesize that infusion of NK cells expressing high levels of the CXCR2 chemokine receptor will result in increased influx of the transferred NK cells into tumors, and improved clinical outcome in patients with cancer. Blood and tumor biopsies from 14 primary RCC patients were assessed by flow cytometry and chemokine analysis. Primary NK cells were transduced with human CXCR2 using a retroviral system. CXCR2 receptor functionality was determined by Calcium flux and NK cell migration was evaluated in transwell assays. We detected higher concentrations of CXCR2 ligands in tumors compared with plasma of RCC patients. In addition, CXCL5 levels correlated with the intratumoral infiltration of CXCR2-positive NK cells. However, tumor-infiltrating NK cells from RCC patients expressed lower CXCR2 compared with peripheral blood NK cells. Moreover, healthy donor NK cells rapidly lost their CXCR2 expression upon in vitro culture and expansion. Genetic modification of human primary NK cells to re-express CXCR2 improved their ability to specifically migrate along a chemokine gradient of recombinant CXCR2 ligands or RCC tumor supernatants compared with controls. The enhanced trafficking resulted in increased killing of target cells. In addition, while their functionality remained unchanged compared with control NK cells, CXCR2-transduced NK cells obtained increased adhesion properties and formed more conjugates with target cells. To increase the success of NK cell-based therapies of solid tumors, it is of great importance to promote their homing to the tumor site. In this study, we show that stable engineering of human primary NK cells to express a chemokine receptor thereby enhancing their migration is a promising strategy to improve anti-tumor responses following adoptive transfer of NK cells. The online version of this article (doi:10.1186/s40425-017-0275-9) contains supplementary material, which is available to authorized users.
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影响因子：
20.3
作者：
Inngjerdingen, M;Damaj, B;Maghazachi, AA
通讯作者：
Maghazachi, AA
用EGFRVIII特异性嵌合抗原受体改装以过表达CXCR4的工程NK细胞可改善CXCL12/SDF-1α分泌胶质母细胞瘤的免疫疗法。
DOI：
10.1097/cji.0000000000000082
发表时间：
2015-06
期刊：
Journal of immunotherapy (Hagerstown, Md. : 1997)
影响因子：
--
作者：
Müller N;Michen S;Tietze S;Töpfer K;Schulte A;Lamszus K;Schmitz M;Schackert G;Pastan I;Temme A
通讯作者：
Temme A
影响因子：
3.9
作者：
Lundqvist, Andreas;Berg, Maria;Childs, Richard W.
通讯作者：
Childs, Richard W.
影响因子：
5.5
作者：
Mishra, Hemant K.;Long, Chunmei;Walcheck, Bruce
通讯作者：
Walcheck, Bruce
影响因子：
4.4
作者：
Campbell, JJ;Qin, SX;Butcher, EC
通讯作者：
Butcher, EC