Lymph Node-Targeted Immunotherapy Mediates Potent Immunity Resulting in Regression of Isolated or Metastatic Human Papillomavirus-Transformed Tumors
Lymph Node-Targeted Immunotherapy Mediates Potent Immunity Resulting in Regression of Isolated or Metastatic Human Papillomavirus-Transformed Tumors
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DOI：
10.1158/1078-0432.ccr-09-0645
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发表时间：
2009-10-01
影响因子：
11.5
通讯作者：
Bot, Adrian
中科院分区：
文献类型：
--
作者：
Smith, Kent A.;Meisenburg, Brenna L.;Bot, Adrian
目的：本研究旨在探讨一种新的免疫治疗策略对HPV16转化的局部或转移性肿瘤的治疗潜力。实验设计：将E749-57抗原和TLR3配体(合成dsRNA)共同免疫携带E7表达肿瘤的动物。用流式细胞仪检测免疫反应，并通过肿瘤大小和生存期来评估抗肿瘤效果。采用原位细胞毒试验、肿瘤浸润性淋巴细胞和T调节细胞鉴定等方法，探讨肿块病治疗耐药的机制。结果：在治疗和预防环境下，免疫可使E749-57抗原特异性T淋巴细胞显著扩增，扩增范围为CD8(+)T细胞的1/10。在肺转移疾病模型中，由此产生的免疫在抑制疾病进展和死亡率方面是有效的。治疗性免疫可以将孤立的肿瘤控制到一定的体积，并与血液中检测的抗肿瘤免疫反应相关。原位分析显示，在巨大的肿瘤中，T细胞功能受到与T调节细胞增加相关的负性调节机制的影响，并可通过环磷酰胺联合免疫治疗来克服。结论：本研究强调了一种新的癌症免疫治疗平台，该平台具有潜在的临床可转移性，并提示该平台在控制转移性疾病、有限大小的实体瘤或较大的肿瘤时具有潜在的作用，可减少肿瘤浸润性T调节细胞的数量。(临床癌症研究2009；15(19)：6167-76)
Purpose: The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic human papillomavirus 16-transformed murine tumors.Experimental Design: Animals bearing E7-expressing tumors were coimmunized by lymph node injection with E7 49-57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and antitumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease.Results: In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen-specific T lymphocytes in the range of 1/10 CD8(+) T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with antitumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T-cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization.Conclusions: This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells. (Clin Cancer Res 2009;15(19):6167-76)