Activation of tumor-specific CD4+ T lymphocytes by major histocompatibility complex class II tumor cell vaccines:: A novel cell-based immunotherapy
Activation of tumor-specific CD4+ T lymphocytes by major histocompatibility complex class II tumor cell vaccines:: A novel cell-based immunotherapy
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DOI：
10.1158/0008-5472.can-03-2634
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发表时间：
2004-03-01
期刊：
影响因子：
11.2
通讯作者：
Ostrand-Rosenberg, S
中科院分区：
文献类型：
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作者：
Dissanayake, SK;Thompson, JA;Ostrand-Rosenberg, S
用同源MHC II类和共刺激分子基因转染的小鼠肿瘤细胞是小鼠中的治疗性疫苗，只要它们不共表达II类相关不变链（Ii）。我们先前证明疫苗细胞通过内源性抗原呈递途径呈递肿瘤肽以激活CD 4（+）和CD 8（+）T细胞。由于它们在小鼠中的有效性，我们正在将这种疫苗策略转化为临床应用。为了获得MHC II类（+）CD 80（+）Ii（-）人肿瘤细胞，我们开发了编码HLA-DR和CD 80的逆转录病毒。HLA-DR病毒使用内部核糖体进入位点编码DR α和DR β 0101链以协调表达。用逆转录病毒DRB 1/CD 80转导的SUM 159 PT乳腺癌和Mel 202眼黑素瘤细胞在不存在Ii的情况下在细胞表面上表达高水平的DRB 0101和CD 80。经辐照的SUM 159 PT/DR 1/CD 80疫苗刺激非HLA-DRB 0101外周血单核细胞的增殖，并呈递外源性DR 1限制性破伤风类毒素（TT）肽，表明转导的DRB 0101是功能性的。用编码TT片段C基因的逆转录病毒作为模型肿瘤抗原进一步转导SUM 159 PT/DR 1/CD 80疫苗。这些细胞刺激IFN-γ从TT-致敏的人DRB 0101外周血单核细胞释放，证明了它们呈递“内源性”肿瘤抗原的能力。耗竭和抗体阻断实验证实，MHC II类限制性内源性合成表位呈递给CD 4（+）T细胞。因此，MHC II类疫苗是有效的抗原呈递细胞，其激活肿瘤特异性MHC II类限制性CD 4（+）T淋巴细胞，并且它们是转移性癌症的新型和潜在的免疫原。
Mouse tumor cells transfected with syngeneic MHC class II and costimulatory molecule genes are therapeutic vaccines in mice, provided they do not coexpress the class II-associated invariant chain (Ii). We demonstrated previously that the vaccine cells present tumor peptides via the endogenous antigen presentation pathway to activate CD4(+) and CD8(+) T cells. Because of their efficacy in mice, we are translating this vaccine strategy for clinical use. To obtain MHC class II(+)CD80(+)Ii(-) human tumor cells, we developed retroviruses encoding HLA-DR and CD80. The HLA-DR virus encodes the DRalpha and DRbeta0101 chains using an internal ribosomal entry site to coordinate expression. SUM159PT mammary carcinoma and Mel 202 ocular melanoma cells transduced with the retroviruses DRB1/CD80 express high levels of DRB0101 and CD80 on the cell surface in the absence of Ii. Irradiated SUM159PT/DR1/CD80 vaccines stimulate proliferation of non-HLA-DRB0101 peripheral blood mononuclear cells and present an exogenous DR1-restricted tetanus toxoid (TT) peptide, indicating that the transduced DRB0101 is functional. SUM159PT/DR1/CD80 vaccines were further transduced with a retrovirus encoding the TT fragment C gene, as a model tumor antigen. These cells stimulate IFN-gamma release from TT-primed human DRB0101 peripheral blood mononuclear cells, demonstrating their ability to present "endogenous" tumor antigen. Depletion and antibody blocking experiments confirm that MHC class II-restricted, endogenously synthesized epitopes are presented to CD4(+) T cells. Therefore, the MHC class II vaccines are efficient antigen-presenting cells that activate tumor-specific MHC class II-restricted, CD4(+) T lymphocytes, and they are a novel and potential immunotherapeutic for metastatic cancers.