Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA.
J Biomed Sci. 2011 Mar 8;18(1):21. doi: 10.1186/1423-0127-18-21.
Antigen-specific immunotherapy using DNA vaccines has emerged as an attractive approach for the control of tumors. Another novel cancer therapy involves the employment of the vascular disrupting agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA). In the current study, we aimed to test the combination of DMXAA treatment with human papillomavirus type 16 (HPV-16) E7 DNA vaccination to enhance the antitumor effects and E7-specific CD8+ T cell immune responses in treated mice. We determined that treatment with DMXAA generates significant therapeutic effects against TC-1 tumors but does not enhance the antigen-specific immune responses in tumor bearing mice. We then found that combination of DMXAA treatment with E7 DNA vaccination generates potent antitumor effects and E7-specific CD8+ T cell immune responses in the splenocytes of tumor bearing mice. Furthermore, the DMXAA-mediated enhancement or suppression of E7-specific CD8+ T cell immune responses generated by CRT/E7 DNA vaccination was found to be dependent on the time of administration of DMXAA and was also applicable to other antigen-specific vaccines. In addition, we determined that inducible nitric oxide synthase (iNOS) plays a role in the immune suppression caused by DMXAA administration before DNA vaccination. Our study has significant implications for future clinical translation.
用 DNA 疫苗进行抗原特异性免疫治疗已成为控制肿瘤的一种有吸引力的方法。另一种新型癌症治疗方法涉及使用血管破坏剂 5,6-二甲基黄嘌呤-4-乙酸（DMXAA）。在本研究中，我们旨在测试 DMXAA 治疗与人乳头瘤病毒 16（HPV-16）E7 DNA 疫苗接种的联合应用，以增强治疗小鼠的抗肿瘤作用和 E7 特异性 CD8+T 细胞免疫反应。我们确定，DMXAA 治疗可显著对抗 TC-1 肿瘤产生治疗效果，但不能增强荷瘤小鼠的抗原特异性免疫反应。然后我们发现，DMXAA 治疗与 E7 DNA 疫苗接种联合应用可在荷瘤小鼠的脾细胞中产生强大的抗肿瘤作用和 E7 特异性 CD8+T 细胞免疫反应。此外，发现 DMXAA 介导的 CRT/E7 DNA 疫苗接种产生的 E7 特异性 CD8+T 细胞免疫反应的增强或抑制取决于 DMXAA 给药的时间，并且也适用于其他抗原特异性疫苗。此外，我们确定诱导型一氧化氮合酶（iNOS）在 DNA 疫苗接种前 DMXAA 给药引起的免疫抑制中起作用。我们的研究对未来的临床转化具有重要意义。
