Self antigens expressed by solid tumors Do not efficiently stimulate naive or activated T cells: implications for immunotherapy.
Self antigens expressed by solid tumors Do not efficiently stimulate naive or activated T cells: implications for immunotherapy.
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实体瘤表达的自抗原不会有效刺激天真或活化的T细胞：对免疫疗法的影响。
DOI：
10.1084/jem.186.5.645
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发表时间：
1997-08-29
期刊：
影响因子：
--
通讯作者：
Ohashi PS
中科院分区：
文献类型：
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作者：
Speiser DE;Miranda R;Zakarian A;Bachmann MF;McKall-Faienza K;Odermatt B;Hanahan D;Zinkernagel RM;Ohashi PS
在体内研究了对原发性内源性肿瘤特异性的细胞毒性T淋巴细胞（CTL）活性的诱导和维持。在大鼠胰岛素启动子（RIP）控制下表达的猿猴病毒40 T抗原（Tag）诱导胰腺β细胞肿瘤产生胰岛素，引起进行性低血糖。作为内源性肿瘤抗原，淋巴细胞性脉络丛脑膜炎病毒（LCMV）糖蛋白（GP）也在RIP的控制下引入。未观察到针对GP的显著自发CTL活化。然而，LCMV感染诱导了抗肿瘤CTL应答，有效地减少了肿瘤质量，导致双转基因RIP（GP × Tag 2）小鼠的血糖水平暂时正常化，并且与对照RIP-Tag 2小鼠（88 ± 8 d）相比延长了存活时间（137 ± 18 d）。令人惊讶的是，尽管肿瘤细胞继续表达MHC I类和LCMV-GP特异性CTL存在且未耐受化，但肿瘤特异性CTL应答并未持续。随后将病毒激活的脾细胞过继转移到RIP（GP × Tag 2）小鼠中进一步延长了存活期（168 ± 11 d），证明LCMV-GP肿瘤抗原和MHC I类的持续表达。数据显示，肿瘤没有自发诱导或维持活化的CTL应答，揭示了体内免疫原性的严重缺乏。因此，重复免疫对于延长抗肿瘤免疫治疗是必要的。此外，这些数据表明，诱导慢性自身免疫性疾病的风险是有限的，这可能会鼓励针对肿瘤选择性但非排他性表达的抗原的免疫治疗。
Induction and maintenance of cytotoxic T lymphocyte (CTL) activity specific for a primary endogenous tumor was investigated in vivo. The simian virus 40 T antigen (Tag) expressed under the control of the rat insulin promoter (RIP) induced pancreatic β-cell tumors producing insulin, causing progressive hypoglycemia. As an endogenous tumor antigen, the lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) was introduced also under the control of the RIP. No significant spontaneous CTL activation against GP was observed. However, LCMV infection induced an antitumor CTL response which efficiently reduced the tumor mass, resulting in temporarily normalized blood glucose levels and prolonged survival of double transgenic RIP(GP × Tag2) mice (137 ± 18 d) as opposed to control RIP-Tag2 mice (88 ± 8 d). Surprisingly, the tumor-specific CTL response was not sustained despite the facts that the tumor cells continued to express MHC class I and LCMV-GP–specific CTLs were present and not tolerized. Subsequent adoptive transfer of virus activated spleen cells into RIP(GP × Tag2) mice further prolonged survival (168 ± 11 d), demonstrating continued expression of the LCMV-GP tumor antigen and MHC class I. The data show that the tumor did not spontaneously induce or maintain an activated CTL response, revealing a profound lack of immunogenicity in vivo. Therefore, repetitive immunizations are necessary for prolonged antitumor immunotherapy. In addition, the data suggest that the risk for induction of chronic autoimmune diseases is limited, which may encourage immunotherapy against antigens selectively but not exclusively expressed by the tumor.