Liau Linda M, Jensen Eric R, Kremen Thomas J, Odesa Sylvia K, Sykes Steven N, Soung Michael C, Miller Jeff F, Bronstein Jeff M
Division of Neurosurgery, Department of Microbiology, Immunology, & Molecular Genetics, School of Medicine, University of California at Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095, USA.
Cancer Res. 2002 Apr 15;62(8):2287-93.
Tumors arising within the central nervous system (CNS) present the immune system with a challenging target, given the heterogeneous nature of these neoplasms and their location within an "immunologically privileged" site. We used the lymphocytic choriomeningitis virus nucleoprotein (LCMV-NP) as a pseudotumor antigen to investigate recombinant Listeria monocytogenes as a tumor vaccine against s.c. and intracerebral challenges with a NP-expressing glioma, 9L-NP. Using Fischer 344 rats, we demonstrate that vaccination with recombinant L. monocytogenes-NP stimulates protection against s.c., but not intracerebral, 9L-NP tumor challenge in an antigen-specific, CD8(+) T-cell-dependent manner. After s.c. tumor rejection, enhanced antitumor immunity is achieved via epitope spreading that permits complete resistance against lethal intracerebral challenge with 9L-NP and with the untransfected parental 9L tumor. Unlike the CD8(+)-dependent immune responses against s.c. 9L-NP tumors, this expanded intracerebral immunity against endogenous tumor-associated antigens is dependent on both CD4(+) and CD8(+) T cells. Taken together, these results demonstrate that the mechanisms of tumor immunity within the brain are different from those elicited against non-CNS tumors. Furthermore, vaccination approaches exploiting the concept of epitope spreading may enhance the efficacy of antitumor immune responses within the immunologically privileged CNS, potentially mediating tumor cell killing through both CD4(+)- and CD8(+)-dependent effector pathways.
鉴于中枢神经系统（CNS）肿瘤的异质性及其位于“免疫特惠”部位的特性，这些肿瘤给免疫系统带来了具有挑战性的靶点。我们使用淋巴细胞性脉络丛脑膜炎病毒核蛋白（LCMV-NP）作为假肿瘤抗原，研究重组单核细胞增生李斯特菌作为针对表达NP的神经胶质瘤9L-NP的皮下和脑内攻击的肿瘤疫苗。使用Fischer 344大鼠，我们证明用重组单核细胞增生李斯特菌-NP疫苗接种以抗原特异性、CD8(+) T细胞依赖性方式刺激针对皮下9L-NP肿瘤攻击的保护作用，但对脑内攻击无效。皮下肿瘤排斥后，通过表位扩展实现增强的抗肿瘤免疫，从而允许对9L-NP和未转染的亲本9L肿瘤的致死性脑内攻击产生完全抗性。与针对皮下9L-NP肿瘤的CD8(+)依赖性免疫反应不同，这种针对内源性肿瘤相关抗原的扩展脑内免疫依赖于CD4(+)和CD8(+) T细胞。综上所述，这些结果表明脑内肿瘤免疫机制不同于针对非CNS肿瘤引发的机制。此外，利用表位扩展概念的疫苗接种方法可能会增强免疫特惠的CNS内抗肿瘤免疫反应的功效，潜在地通过CD4(+)和CD8(+)依赖性效应途径介导肿瘤细胞杀伤。
