An inducible mouse model of melanoma expressing a defined tumor antigen
An inducible mouse model of melanoma expressing a defined tumor antigen
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DOI：
10.1158/0008-5472.can-05-3216
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发表时间：
2006-03-15
期刊：
影响因子：
11.2
通讯作者：
Van den Eynde, BJ
中科院分区：
文献类型：
--
作者：
Huijbers, IJ;Krimpenfort, P;Van den Eynde, BJ
尽管在临床前模型中取得了有希望的结果，但基于特定肿瘤抗原疫苗接种的癌症免疫疗法尚未显示出强大的临床疗效。这种差异可能是由于现有的临床前模型依赖于可移植肿瘤，而这些模型并不能概括患者在肿瘤进展过程中发生的长期宿主-肿瘤相互作用并导致肿瘤耐受。为了创建一个忠实的癌症免疫治疗临床前模型，我们培育了一种转基因小鼠品系，该品系可产生自体黑色素瘤，表达 T 细胞识别的特定肿瘤抗原。我们选择了 PIA 编码的抗原，PIA 是一种充分表征的小鼠癌症种系基因。为了转化黑色素细胞，我们的目标是同时激活 Ras 通路并失活肿瘤抑制因子 Ink4a/Arf，从而重现人类黑色素瘤中常见的两个遗传事件。黑色素瘤是由皮下注射诱发的。注射4-OH-他莫昔芬（OHT）。通过激活黑色素细胞特异性启动子表达的 CreER 重组酶，该治疗可诱导黑色素细胞中条件性 Ink4a/Arf 基因的丢失。由于 CreER 基因本身的侧翼也有 loxP 位点，因此 CreER 的激活也会诱导其自身编码序列的删除，从而允许位于同一转基因下游的基因 H-ras 和 PIA 的黑素细胞特异性表达。 OHT 小鼠中诱导的所有黑色素瘤均显示 Ras 通路激活和 Ink4a/Arf 基因缺失。此外，这些黑色素瘤表达PIA并被PIA特异性T淋巴细胞识别。该模型将能够表征免疫系统和自然发生的肿瘤之间的相互作用，从而优化针对特定肿瘤抗原的免疫治疗方法。
Cancer immunotherapy based on vaccination with defined tumor antigens has not yet shown strong clinical efficacy, despite promising results in preclinical models. This discrepancy might result from the fact that available preclinical models rely on transplantable tumors, which do not recapitulate the long-term host-tumor interplay that occurs in patients during progressive tumor development and results in tumor tolerance. To create a faithful preclinical model for cancer immunotherapy, we generated a transgenic mouse strain developing autologous melanomas expressing a defined tumor antigen recognized by T cells. We chose the antigen encoded by PIA, a well-characterized murine cancer germ line gene. To transform melanocytes, we aimed at simultaneously activating the Ras pathway and inactivating tumor suppressor Ink4a/Arf, thereby reproducing two genetic events frequently observed in human melanoma. The melanomas are induced by s.c. injection of 4-OH-tamoxifen (OHT). By activating a CreER recombinase expressed from a melanocyte-specific promoter, this treatment induces the loss of the conditional Ink4a/Arf gene in melanocytes. Because the CreER gene itself is also flanked by loxP sites, the activation of CreER also induces the deletion of its own coding sequence and thereby allows melanocyte-specific expression of genes H-ras and PIA, which are located downstream on the same transgene. All melanomas induced in those mice with OHT show activation of the Ras pathway and deletion of gene Ink4a/Arf. In addition, these melanomas express PIA and are recognized by PIA-specific T lymphocytes. This model will allow to characterize the interactions between the immune system and naturally occurring tumors and thereby to optimize immunotherapy approaches targeting a defined tumor antigen.