Sherritt M, Cooper L, Moss D J, Kienzle N, Altman J, Khanna R
Tumour Immunology Laboratory, Epstein-Barr Virus Unit, Queensland Institute of Medical Research and University of Queensland Joint Oncology Program, Bancroft Centre, 300 Herston Road, Brisbane, Queensland 4029, Australia.
Int Immunol. 2001 Mar;13(3):265-71. doi: 10.1093/intimm/13.3.265.
Treatment of human cancers with an inherent antigen-processing defect due to a loss of peptide transporters (TAP-1 and TAP-2) and/or MHC class I antigen expression remains a considerable challenge. There is now an increasing realization that tumor cells with down-regulated expression of TAP and/or MHC class I antigens display strong resistance to cytotoxic T lymphocyte (CTL)-mediated immune control, and often fail to respond to the conventional immunotherapeutic protocols based on active immunization with tumor-associated epitopes (TAE) or adoptive transfer of tumor-specific T cells. In the present study, we describe a novel approach based on immunization with either genetically modified tumor cells or naked DNA vectors encoding TAE fused to an endoplasmic reticulum (ER) signal sequence (ER-TAE) which affords protection against challenge by melanoma cells with down-regulated expression of TAP-1/2 and MHC class I antigens. In contrast, animals immunized with a vaccine based on TAE alone showed no protection against tumor challenge. Although MHC-peptide tetramer analysis showed a similar frequency of antigen-specific CTL in both ER-TAE- and TAE-immunized mice, functional analysis revealed that CTL activated following immunization with ER-TAE displayed significantly higher avidity for TAE when compared to animals immunized with the TAE alone. These observations provide a new strategy in anti-cancer vaccine design that allows activation of a highly effective and well-defined CTL response against tumors with down-regulated expression of TAP and MHC class I antigens.
由于肽转运体（TAP-1和TAP-2）缺失和/或MHC I类抗原表达而具有内在抗原加工缺陷的人类癌症的治疗仍然是一项重大挑战。现在越来越认识到，TAP和/或MHC I类抗原表达下调的肿瘤细胞对细胞毒性T淋巴细胞（CTL）介导的免疫控制表现出强烈抗性，并且通常对基于肿瘤相关表位（TAE）主动免疫或肿瘤特异性T细胞过继转移的传统免疫治疗方案无反应。在本研究中，我们描述了一种基于用基因修饰的肿瘤细胞或编码与内质网（ER）信号序列融合的TAE（ER-TAE）的裸DNA载体进行免疫的新方法，该方法可提供针对TAP-1/2和MHC I类抗原表达下调的黑色素瘤细胞攻击的保护作用。相比之下，仅用基于TAE的疫苗免疫的动物对肿瘤攻击没有保护作用。虽然MHC-肽四聚体分析显示在ER-TAE免疫小鼠和TAE免疫小鼠中抗原特异性CTL的频率相似，但功能分析表明，与仅用TAE免疫的动物相比，用ER-TAE免疫后激活的CTL对TAE表现出明显更高的亲和力。这些观察结果为抗癌疫苗设计提供了一种新策略，该策略允许激活针对TAP和MHC I类抗原表达下调的肿瘤的高效且明确的CTL反应。
