Cancer immunotherapy targeting the high molecular weight melanoma-associated antigen protein results in a broad antitumor response and reduction of pericytes in the tumor vasculature
Cancer immunotherapy targeting the high molecular weight melanoma-associated antigen protein results in a broad antitumor response and reduction of pericytes in the tumor vasculature
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DOI：
10.1158/0008-5472.can-08-0287
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发表时间：
2008-10-01
期刊：
影响因子：
11.2
通讯作者：
Paterson, Yvonne
中科院分区：
文献类型：
--
作者：
Maciag, Paulo Cesar;Seavey, Matthew M.;Paterson, Yvonne
高分子量黑色素瘤相关抗原（HMW-MAA），也称为黑色素瘤硫酸软骨素蛋白聚糖，已被用作黑色素瘤免疫治疗的靶标。该抗原表达于细胞表面，并在正常组织中具有有限的分布。除了在广泛的转化细胞中表达外，该抗原还存在于周细胞中，周细胞对肿瘤血管生成很重要。我们产生了重组单核细胞增多性李斯特菌（Lm-LLO-HMW-MAA-C），其表达并分泌融合至嗜酸乳杆菌溶血素O（LLO）蛋白的前441个残基的HMW-MAA片段（残基2，160 - 2，258）。用Lm-LLO-HMW-MAA-C免疫能够阻止小鼠中早期建立的B16 F10-HMW-MAA肿瘤的肿瘤生长，并且治疗功效需要CD 4（+）和CD 8（+）T细胞。在用Lm-LLO-HMW-MAA-C免疫的HLA-A2/K-b转基因小鼠中检测到对HMW-MAA（2160-2258）片段中存在的已知HLA-A2表位的免疫应答。令人惊讶的是，这种疫苗还显著损害了其他致瘤细胞系的体内生长，如黑色素瘤、肾癌和乳腺肿瘤，这些细胞系未被工程化以表达HMW-MAA。一种假设是，疫苗可以靶向周细胞，这对肿瘤血管生成很重要。在乳腺肿瘤模型中，Lm-LLO-HMW-MAA-C免疫导致肿瘤间质中CD 8（+）T细胞浸润以及肿瘤血管中周细胞数量显着减少。总之，针对HMW-MAA的基于Lm的疫苗可以触发针对该抗原的细胞介导的免疫应答，其不仅可以靶向肿瘤细胞，而且可以靶向肿瘤脉管系统中的周细胞。
The high molecular weight melanoma-associated antigen (HMW-MAA), also known as melanoma chondroitin sulfate proteoglycan, has been used as a target for the immunotherapy of melanoma. This antigen is expressed on the cell surface and has a restricted distribution in normal tissues. Besides its expression in a broad range of transformed cells, this antigen is also found in pericytes, which are important for tumor angiogenesis. We generated a recombinant Listeria monocytogenes (Lm-LLO-HMW-MAA-C) that expresses and secretes a fragment of HMW-MAA (residues 2,160-2,258) fused to the first 441 residues of the listeriolysin O (LLO) protein. Immunization with Lm-LLO-HMW-MAA-C was able to impede the tumor growth of early established B16F10-HMW-MAA tumors in mice and both CD4(+) and CD8(+) T cells were required for therapeutic efficacy. Immune responses to a known HLA-A2 epitope present in the HMW-MAA(2160-2258) fragment was detected in the HLA-A2/K-b transgenic mice immunized with Lm-LLO-HMW-MAA-C. Surprisingly, this vaccine also significantly impaired the in vivo growth of other tumorigenic cell lines, such as melanoma, renal carcinoma, and breast tumors, which were not engineered to express HMW-MAA. One hypothesis is that the vaccine could be targeting pericytes, which are important for tumor angiogenesis. In a breast tumor model, immunization with Lm-LLO-HMW-MAA-C caused CD8(+) T-cell infiltration in the tumor stroma and a significant decrease in the number of pericytes in the tumor blood vessels. In conclusion, a Lm-based vaccine against HMW-MAA can trigger cell-mediated immune responses to this antigen that can target not only tumor cells but also pericytes in the tumor vasculature.