Therapeutic efficacy of antigen-specific vaccination and toll-like receptor stimulation against established transplanted and autochthonous melanoma in mice.
Therapeutic efficacy of antigen-specific vaccination and toll-like receptor stimulation against established transplanted and autochthonous melanoma in mice.
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DOI：
10.1097/00008390-200609001-00078
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发表时间：
2006-05
期刊：
影响因子：
11.2
通讯作者：
D. Tormo;Aleix Ferrer;P. Bosch;E. Gaffal;E. Basner-Tschakarjan;J. Wenzel;T. Tüting
中科院分区：
文献类型：
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作者：
D. Tormo;Aleix Ferrer;P. Bosch;E. Gaffal;E. Basner-Tschakarjan;J. Wenzel;T. Tüting
恶性黑色素瘤是一个有吸引力的模型疾病的抗原特异性免疫治疗的发展，因为许多抗原识别的肿瘤特异性T细胞已被确定。在C57 BL/6小鼠中，用编码异种人酪氨酸酶相关蛋白2（Ad-hTRP 2）的重组腺病毒进行基因免疫诱导针对移植的B16黑色素瘤细胞生长的保护性而非治疗性细胞免疫。在这里，我们还应用了CpG DNA和合成的双链RNA，它们通过Toll样受体（TLR）激活先天免疫系统。腺病毒疫苗接种和肿瘤周围注射TLR配体是皮肤中建立的B16黑色素瘤排斥反应所必需的。为了更接近地模拟黑色素瘤患者的临床情况，我们在转基因小鼠中评估了这种联合免疫策略，该转基因小鼠过表达肝细胞生长因子（HGF）并携带细胞周期蛋白依赖性激酶4（CDK 4）（R24 C）的致癌突变。HGF x CDK 4（R24 C）小鼠在新生儿致癌物治疗后迅速在皮肤中形成多发性侵袭性黑色素瘤，其自发转移到淋巴结和肺。Ad-hTRP 2疫苗接种后注射TLR配体导致皮肤原发性黑色素瘤生长延迟，自发性肺转移数量减少，但不诱导肿瘤消退。致癌剂处理的HGF x CDK 4（R24 C）小鼠携带多个自体黑色素瘤没有排斥移植的B16黑色素瘤，尽管与Ad-hTRP 2和TLR配体治疗，表明肿瘤免疫耐受的发展。在我们的新型遗传性黑色素瘤模型中的进一步研究可能有助于更好地了解免疫系统在这种危及生命的疾病的发病机制和治疗中的作用。
Malignant melanoma is an attractive model disease for the development of antigen-specific immunotherapy because many antigens recognized by tumor-specific T cells have been identified. In C57BL/6 mice, genetic immunization with recombinant adenovirus encoding xenogeneic human tyrosinase-related protein 2 (Ad-hTRP2) induces protective but not therapeutic cellular immunity against growth of transplanted B16 melanoma cells. Here, we additionally applied CpG DNA and synthetic double-stranded RNA, which activate the innate immune system via Toll-like receptors (TLR). Both adenoviral vaccination and peritumoral injections of TLR ligands were required for rejection of established B16 melanoma in the skin. To more closely mimic the clinical situation in patients with melanoma, we evaluated this combined immunotherapeutic strategy in genetically modified mice, which overexpress hepatocyte growth factor (HGF) and carry an oncogenic mutation in the cyclin-dependent kinase 4 (CDK4)(R24C). HGF x CDK4(R24C) mice rapidly develop multiple invasive melanomas in the skin following neonatal carcinogen treatment, which spontaneously metastasize to lymph nodes and lungs. Vaccination with Ad-hTRP2 followed by injections of TLR ligands resulted in delayed growth of autochthonous primary melanomas in the skin and reduction in the number of spontaneous lung metastases but did not induce tumor regression. Carcinogen-treated HGF x CDK4(R24C) mice bearing multiple autochthonous melanomas did not reject transplanted B16 melanoma despite treatment with Ad-hTRP2 and TLR ligands, suggesting the development of tumor immunotolerance. Further investigations in our novel genetic melanoma model may help to better understand the role of the immune system in the pathogenesis and treatment of this life-threatening disease.