Wennerberg Erik, Kremer Veronika, Childs Richard, Lundqvist Andreas
Department of Oncology-Pathology, Cancer Center Karolinska, R8:01, Karolinska Institutet, 171 76, Stockholm, Sweden.
Cancer Immunol Immunother. 2015 Feb;64(2):225-35. doi: 10.1007/s00262-014-1629-5. Epub 2014 Oct 26.
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.
尽管目前临床反应仅限于血液系统恶性肿瘤患者，但过继性输注自然杀伤（NK）细胞作为一种癌症治疗方法正越来越多地被探索。输注的NK细胞向肿瘤部位的归巢不足是一个关键因素，这可能解释了NK细胞疗法对实体瘤的抗肿瘤效果不佳的原因。淋巴细胞趋化性调节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（CXCR3），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（CXCL9、10和11）梯度迁移。在此，我们表明，与静息NK细胞相比，人NK细胞的体外扩增导致CXCR3受体表达增加了10倍（p = 0.04）。因此，这些NK细胞对实体瘤的迁移能力有所改善，这取决于肿瘤来源的CXCL10。在异种移植模型中，与CXCL10阴性的野生型肿瘤相比，过继性转移的NK细胞对CXCL10转染的黑色素瘤肿瘤的迁移增加，导致肿瘤负担显著减轻和生存期延长（中位生存期41天对32天，p = 0.03）。此外，在肿瘤局部给予干扰素-γ刺激皮下黑色素瘤肿瘤中CXCL10的产生，导致过继性转移的CXCR3阳性扩增NK细胞浸润增加。我们的研究结果证明了CXCL10诱导的化学趋化作用在过继性转移的扩增NK细胞对实体黑色素瘤肿瘤的抗肿瘤反应中的重要性。
