Natural Killer T-cell Immunotherapy in Combination with Chemotherapy-Induced Immunogenic Cell Death Targets Metastatic Breast Cancer
Natural Killer T-cell Immunotherapy in Combination with Chemotherapy-Induced Immunogenic Cell Death Targets Metastatic Breast Cancer
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DOI：
10.1158/2326-6066.cir-17-0229
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发表时间：
2017-12-01
影响因子：
10.1
通讯作者：
Johnston, Brent
中科院分区：
文献类型：
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作者：
Gebremeskel, Simon;Lobert, Lynnea;Johnston, Brent
自然杀伤T细胞（NKT）是促进癌症控制的糖脂反应性淋巴细胞。在先前的研究中，nkt细胞激活可改善转移性乳腺癌术后小鼠模型的存活和抗肿瘤免疫。在此，我们研究了nkt细胞活化是否可以与化疗药物联合使用以提高治疗效果。吉西他滨和环磷酰胺类似物通过增加抗原呈递分子（MHC-I、MHC-II和CD1d）的表达和促进免疫原性细胞死亡标志物（钙网蛋白、HMGB1和ATP）的暴露或释放，增强了4T1乳腺癌细胞的潜在免疫原性。在4T1原发肿瘤和术后转移模型中，BALB/c小鼠接受环磷酰胺或吉西他滨治疗。然后通过装载糖脂抗原-半乳糖神经酰胺（α - galcer）的树突状细胞转移激活NKT细胞。化疗治疗不影响nkt细胞活化，但增强了向原发肿瘤的募集。环磷酰胺、吉西他滨或负载a- galcer的树突状细胞单药治疗在原发肿瘤模型中降低肿瘤生长，在转移模型中降低转移负担并延长生存期。将化疗药物与nkt细胞活化疗法相结合可显著提高生存率，存活小鼠在第二次肿瘤攻击后表现出肿瘤生长减弱。吉西他滨、环磷酰胺或装载α - galcer的树突状细胞治疗可降低髓源性抑制细胞的频率；环磷酰胺也降低了调节性T细胞的频率。单独治疗增加了免疫细胞活化、细胞因子极化和细胞毒性反应，尽管这些读数并没有通过联合治疗进一步增强。这些发现表明，nkt细胞活化疗法可以联合吉西他滨或环磷酰胺靶向肿瘤负荷，增强对肿瘤复发的保护作用。(c) 2017 aacr。
Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a postsurgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogues enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1, and ATP). In 4T1 primary tumor and postsurgical metastasis models, BALB/c mice were treated with cyclophosphamide or gemcitabine. NKT cells were then activated by transfer of dendritic cells loaded with the glycolipid antigen a-galactosylceramide (alpha-GalCer). Chemotherapeutic treatments did not impact NKT-cell activation but enhanced recruitment into primary tumors. Cyclophosphamide, gemcitabine, or a-GalCer-loaded dendritic cell monotherapies decreased tumor growth in the primary tumor model and reduced metastatic burden and prolonged survival in the metastasis model. Combining chemotherapeutics with NKT-cell activation therapy significantly enhanced survival, with surviving mice exhibiting attenuated tumor growth following a second tumor challenge. The frequency of myeloidderived suppressor cells was reduced by gemcitabine, cyclophosphamide, or alpha-GalCer-loaded dendritic cell treatments; cyclophosphamide also reduced the frequency of regulatory T cells. Individual treatments increased immune cell activation, cytokine polarization, and cytotoxic responses, although these readouts were not enhanced further by combining therapies. These findings demonstrate that NKT-cell activation therapy can be combined with gemcitabine or cyclophosphamide to target tumor burden and enhance protection against tumor recurrence. (C) 2017 AACR.