Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.
Combining antiangiogenic therapy with adoptive cell immunotherapy exerts better antitumor effects in non-small cell lung cancer models.
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抗血管生成治疗与过继性细胞免疫治疗相结合，在非小细胞肺癌模型中发挥更好的抗肿瘤作用。
DOI：
10.1371/journal.pone.0065757
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Huang G
中科院分区：
文献类型：
--
作者：
Shi S;Wang R;Chen Y;Song H;Chen L;Huang G
细胞因子诱导的杀伤细胞（CIK细胞）是体外扩增的T淋巴细胞的异质亚群，其特征在于具有MHC不受限制的肿瘤杀伤活性和混合的T-NK表型。作为过继免疫疗法之一的CIK细胞移植是一种很有前途的无毒抗肿瘤治疗方法。然而，在临床研究中，过继CIK细胞转移的治疗活性并不像预期的那样有效。可能的解释是异常的肿瘤血管和缺氧的肿瘤微环境可能会阻碍淋巴细胞的浸润和功效。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缺氧肿瘤微环境来提高CIK细胞的抗肿瘤活性。我们将重组人内皮抑素（rh-endostatin）与CIK细胞联合应用于小鼠肺癌模型的治疗。活体显微镜、动态增强磁共振成像、免疫组化和流式细胞术用于研究肿瘤血管和缺氧微环境以及免疫细胞浸润。结果表明，rh-endostatin与过继性CIK细胞联合转染对肺癌的生长有协同抑制作用。我们发现，rh-endostatin使肿瘤血管正常化，并减少肿瘤微环境中的缺氧区域。缺氧可显著抑制CIK细胞的体外增殖、细胞毒活性和迁移能力，并阻碍CIK细胞在体内归巢。此外，我们发现用rh-endostatin治疗显著增加了CIK细胞的归巢，并减少了肿瘤组织中抑制性免疫细胞的积累。此外，与其他治疗相比，联合治疗产生更高水平的肿瘤浸润淋巴细胞。结果表明，rh-endostatin可提高过继CIK细胞治疗肺癌的疗效，并揭示其协同抗肿瘤作用的机制，为抗血管生成治疗与免疫治疗联合应用治疗肺癌提供了新的理论依据。
Cytokine-induced killer cells (CIK cells) are a heterogeneous subset of ex-vivo expanded T lymphocytes which are characterized with a MHC-unrestricted tumor-killing activity and a mixed T-NK phenotype. Adoptive CIK cells transfer, one of the adoptive immunotherapy represents a promising nontoxic anticancer therapy. However, in clinical studies, the therapeutic activity of adoptive CIK cells transfer is not as efficient as anticipated. Possible explanations are that abnormal tumor vasculature and hypoxic tumor microenvironment could impede the infiltration and efficacy of lymphocytes. We hypothesized that antiangiogenesis therapy could improve the antitumor activity of CIK cells by normalizing tumor vasculature and modulating hypoxic tumor microenvironment. We combined recombinant human endostatin (rh-endostatin) and CIK cells in the treatment of lung carcinoma murine models. Intravital microscopy, dynamic contrast enhanced magnetic resonance imaging, immunohistochemistry, and flow cytometry were used to investigate the tumor vasculature and hypoxic microenvironment as well as the infiltration of immune cells. Our results indicated that rh-endostatin synergized with adoptive CIK cells transfer to inhibit the growth of lung carcinoma. We found that rh-endostatin normalized tumor vasculature and reduced hypoxic area in the tumor microenvironment. Hypoxia significantly inhibited the proliferation, cytotoxicity and migration of CIK cells in vitro and impeded the homing of CIK cells into tumor parenchyma ex vivo. Furthermore, we found that treatment with rh-endostatin significantly increased the homing of CIK cells and decreased the accumulation of suppressive immune cells in the tumor tissue. In addition, combination therapy produced higher level of tumor-infiltration lymphocytes compared with other treatments. Our results demonstrate that rh-endostatin improves the therapeutic effect of adoptive CIK cells therapy against lung carcinomas and unmask the mechanisms of the synergistic antitumor efficacy, providing a new rationale for combining antiangiogenesis therapy with immunotherapy in the treatment of lung cancer.
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DOI：
10.3109/02656731003601745
发表时间：
2010
期刊：
International journal of hyperthermia : the official journal of European Society for Hyperthermic Oncology, North American Hyperthermia Group
影响因子：
--
作者：
Lee CT;Mace T;Repasky EA
通讯作者：
Repasky EA
表皮生长因子受体抑制通过血管正常化调节微环境，从而提高化疗和放疗疗效。
影响因子：
3.7
作者：
Cerniglia, George J.;Pore, Nabendu;Tsai, Jeff H.;Schultz, Susan;Mick, Rosemarie;Choe, Regine;Xing, Xiaoman;Durduran, Turgut;Yodh, Arjun G.;Evans, Sydney M.;Koch, Cameron J.;Hahn, Stephen M.;Quon, Harry;Sehgal, Chandra M.;Lee, William M. F.;Maity, Amit
通讯作者：
Maity, Amit
影响因子：
5.3
作者：
Jiang, Xiao-dong;Dai, Peng;Yu, Jin-ming
通讯作者：
Yu, Jin-ming
DOI：
10.1073/pnas.1113744109
发表时间：
2012-02-14
影响因子：
11.1
作者：
Cortez-Retamozo, Virna;Etzrodt, Martin;Pittet, Mikael J.
通讯作者：
Pittet, Mikael J.
影响因子：
2.5
作者：
Javaherian, Kashi;Lee, Tong-Young;Hlatky, Lynn
通讯作者：
Hlatky, Lynn