In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the alpha1,3galactosyltransferase gene.
In vivo targeting of vaccinating tumor cells to antigen-presenting cells by a gene therapy method with adenovirus containing the alpha1,3galactosyltransferase gene.
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通过基因治疗方法，使用含有 α1,3 半乳糖基转移酶基因的腺病毒，在体内将肿瘤细胞接种到抗原呈递细胞。
DOI：
10.1038/sj.cgt.7700812
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Galili,Uri
中科院分区：
文献类型：
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作者：
Deriy,Lucy;Ogawa,Haruko;Gao,Guang-Ping;Galili,Uri
抗原提呈细胞(APC)摄取能力差是自体肿瘤疫苗免疫原性低的主要原因。这种免疫原性可以通过利用天然的抗Gal抗体来提高，这种抗体存在于人类体内，是循环∼的1%。抗-Gal与α-Gal表位(Galα1-3GalGalβ1-4GlcNAc-R)免疫肿瘤细胞，并使其被APC有效摄取。该表位是用AdαGT-一种含有α-1，3-半乳糖基转移酶(α-1，3GT)基因的复制缺陷型腺病毒在人肿瘤细胞中合成的。用高致瘤性α-GT黑色素瘤细胞攻击α-1、3GT基因敲除(KO)小鼠，研究了Ad-BLGT转导的肿瘤细胞免疫对肿瘤的保护作用。这些小鼠缺乏α-Gal表位，可以产生抗Gal。用AdαGT转导的BL6细胞免疫KO小鼠，可保护许多小鼠免受缺乏α-Gal表位的BL6细胞的攻击。用AdαGT转导的自体肿瘤细胞免疫可作为标准治疗完成后的辅助免疫治疗。这种方法可能是对另一种基因治疗方法的补充，在这种方法中，分泌GM-CSF的肿瘤细胞将APC招募到接种部位。抗Gal调理疫苗接种的肿瘤细胞将被GM-CSF募集的APC有效地内化，并被运送到引流淋巴结处理和呈递肿瘤抗原。或者，将AdαGT直接注射到癌症患者的实体瘤中，可能会导致抗Gal介导的肿瘤细胞以类似于异种移植排斥反应的方式被破坏。APC随后摄取抗半乳糖化的肿瘤膜，使其有效地转运到淋巴结，在那里处理的肿瘤抗原可能会引发保护性的抗肿瘤免疫反应。
Poor uptake by antigen-presenting cells (APC) is a major reason for low immunogenicity of autologous tumor vaccines. This immunogenicity may be increased by exploiting the natural anti-Gal antibody that is present in humans as∼ 1% of circulating IgG. Anti-Gal binds to α-gal epitopes (Galα1-3Galβ1-4GlcNAc-R) on vaccinating tumor cells and opsonizes them for effective uptake by APC. This epitope is synthesized in human tumor cells by transduction with AdαGT-a replication deficient adenovirus containing the α1, 3galactosyltransferase (α1, 3GT) gene. Protection against tumors by immunization with AdαGT-transduced tumor cells was studied in α1, 3GT knockout (KO) mice, challenged with the highly tumorigenic BL6 melanoma cells. These mice lack α-gal epitopes and can produce anti-Gal. Immunization of KO mice with AdαGT-transduced BL6 cells protects many of the mice against challenge with live BL6 cells lacking α-gal epitopes. Immunization with AdαGT transduced autologous tumor cells may serve as adjuvant immunotherapy delivered after completion of standard therapy. This method may complement another gene therapy method in which GM-CSF-secreting vaccinating tumor cells recruit APC to vaccination sites. Anti-Gal-opsonized vaccinating tumor cells will be effectively internalized by GM-CSF recruited APC and transported to draining lymph nodes for processing and presentation of tumor antigens. Alternatively, injection of AdαGT directly into solid tumor masses of cancer patients may result in anti-Gal-mediated destruction of the transduced tumor cells in a manner similar to xenograft rejection. The subsequent uptake of anti-Gal-opsonized tumor membranes by APC results in their effective transportation to lymph nodes where processed tumor antigens may elicit a protective antitumor immune response.