Bevacizumab improves the antitumor efficacy of adoptive cytokine-induced killer cells therapy in non-small cell lung cancer models
Bevacizumab improves the antitumor efficacy of adoptive cytokine-induced killer cells therapy in non-small cell lung cancer models
复制标题
贝伐珠单抗提高非小细胞肺癌模型中过继细胞因子诱导的杀伤细胞疗法的抗肿瘤功效
DOI：
10.1007/s12032-013-0777-3
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发表时间：
2014-01-01
期刊：
影响因子：
3.4
通讯作者：
Chen, Longbang
中科院分区：
文献类型：
--
作者：
Tao, Leilei;Huang, Guichun;Chen, Longbang
细胞因子诱导的杀伤细胞（CIK细胞）是由外周血单个核细胞产生的异质细胞群，其与自然杀伤细胞和T细胞具有相同的表型和功能特性。CIK细胞作为一种过继性免疫疗法，具有较强的体外抗肿瘤活性，是治疗多种恶性肿瘤的有效方法。然而，CIK细胞治疗的临床试验并未显示出预期的治愈率或长期生存率的明显改善。可能的解释是异常的肿瘤血管和缺氧微环境可能高度限制CIK细胞治疗的治疗益处。我们推测，抗血管生成治疗可以通过正常化肿瘤血管和调节肿瘤缺氧微环境来增强CIK细胞的抗肿瘤功效。在这项研究中，我们联合贝伐单抗和过继CIK细胞治疗肺腺癌小鼠模型。应用流式细胞术、活体显微镜和免疫组化技术检测肿瘤血管、缺氧微环境和CIK细胞浸润情况。结果表明，贝伐珠单抗联合过继CIK细胞对肺腺癌的生长具有协同抑制作用。缺氧明显抑制CIK细胞向肿瘤组织的浸润。贝伐单抗可使肿瘤血管正常化，减少肿瘤缺氧面积。联合治疗能促进CIK细胞向肿瘤内的浸润。贝伐珠单抗提高CIK细胞转移治疗非小细胞肺癌（NSCLC）的抗肿瘤疗效。本研究为晚期非小细胞肺癌患者抗血管生成治疗联合CIK细胞治疗提供了一种合理、有益的策略。
Cytokine-induced killer cells (CIK cells) are a heterogeneous population of cells generated from peripheral blood mononuclear cells, which share phenotypic and functional properties with both natural killer and T cells. CIK cells therapy, as an adoptive immunotherapy with strong antitumor activity in vitro, represents a promising approach for the treatment of a broad array of malignant tumors. However, clinical trials in CIK cells therapy did not show more noticeable improvement as anticipated in cure rates or long-term survival. Possible explanations are that abnormal tumor vasculature and hypoxic microenvironment may highly limit the therapeutic benefits of CIK cells therapy. We hypothesized that antiangiogenesis therapy could enhance the antitumor efficacy of CIK cells by normalizing tumor vasculature and modulating tumor hypoxic microenvironment. In this study, we combined bevacizumab and adoptive CIK cells therapy in the treatment of lung adenocarcinoma bearing murine models. Flow cytometry, intravital microscopy and immunohistochemistry were applied to detect tumor vasculature and hypoxic microenvironment as well as the infiltration of CIK cells. The results indicated that bevacizumab-combined adoptive CIK cells had synergistic inhibition effects on the growth of lung adenocarcinoma. Hypoxia significantly inhibited the infiltration of CIK cells into tumor tissue. Bevacizumab could normalize tumor vasculature and decrease tumor hypoxic area. Furthermore, combination therapy enhanced more CIK cells infiltrated into tumor compared with other treatment. Bevacizumab improves antitumor efficacy of CIK cells transfer therapy in non-small cell lung cancer (NSCLC). The study provides a reasonable and beneficial strategy that combined antiangiogenesis therapy with CIK cells therapy for patients of advanced stage non-small cell lung cancer.