CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo
CXCL10-induced migration of adoptively transferred human natural killer cells toward solid tumors causes regression of tumor growth in vivo
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DOI：
10.1007/s00262-014-1629-5
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发表时间：
2015-02-01
影响因子：
5.8
通讯作者：
Lundqvist, Andreas
中科院分区：
文献类型：
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作者：
Wennerberg, Erik;Kremer, Veronika;Lundqvist, Andreas
自然杀伤（NK）细胞的连续输注正越来越多地被探索作为癌症患者的治疗方法，尽管迄今为止临床反应仅限于血液恶性肿瘤患者。输注的NK细胞向肿瘤部位的归巢不足是可能解释NK细胞疗法对实体瘤的抗肿瘤效果差的关键因素。调节淋巴细胞趋化性的主要参与者之一是趋化因子受体趋化因子（C-X-C基序）受体3（CXCR 3），其在活化的NK细胞上表达并诱导NK细胞向趋化因子（C-X-C基序）配体的梯度迁移（CXCL 9、10和11）。在这里，我们表明，人NK细胞的离体扩增导致CXCR3受体的表达与静息NK细胞相比增加了10倍（p = 0.04）。因此，这些NK细胞显示出改善的向实体瘤迁移的能力，这依赖于肿瘤来源的CXCL10。在异种移植模型中，与CXCL10阴性野生型肿瘤相比，过继转移的NK细胞显示出向CXCL10转染的黑色素瘤肿瘤的迁移增加，导致肿瘤负荷显著降低和生存期增加（中位生存期为41 vs. 32天，p = 0. 03）。此外，在肿瘤中局部施用干扰素-γ刺激皮下黑素瘤肿瘤中CXCL10的产生，导致过继转移的CXCR3阳性扩增NK细胞的浸润增加。我们的研究结果证明了CXCL10诱导的化学吸引在过继转移的扩增NK细胞对实体黑色素瘤的抗肿瘤反应中的重要性。
Adoptive infusion of natural killer (NK) cells is being increasingly explored as a therapy in patients with cancer, although clinical responses are thus far limited to patients with hematological malignancies. Inadequate homing of infused NK cells to the tumor site represents a key factor that may explain the poor anti-tumor effect of NK cell therapy against solid tumors. One of the major players in the regulation of lymphocyte chemotaxis is the chemokine receptor chemokine (C-X-C motif) receptor 3 (CXCR3) which is expressed on activated NK cells and induces NK cell migration toward gradients of the chemokine (C-X-C motif) ligand (CXCL9, 10 and 11). Here, we show that ex vivo expansion of human NK cells results in a tenfold increased expression of the CXCR3 receptor compared with resting NK cells (p = 0.04). Consequently, these NK cells displayed an improved migratory capacity toward solid tumors, which was dependent on tumor-derived CXCL10. In xenograft models, adoptively transferred NK cells showed increased migration toward CXCL10-transfected melanoma tumors compared with CXCL10-negative wild-type tumors, resulting in significantly reduced tumor burden and increased survival (median survival 41 vs. 32 days, p = 0.03). Furthermore, administration of interferon-gamma locally in the tumor stimulated the production of CXCL10 in subcutaneous melanoma tumors resulting in increased infiltration of adoptively transferred CXCR3-positive expanded NK cells. Our findings demonstrate the importance of CXCL10-induced chemoattraction in the anti-tumor response of adoptively transferred expanded NK cells against solid melanoma tumors.