Wong C P, Okada C Y, Levy R
Department of Medicine, Division of Oncology, Stanford University School of Medicine, CA 94305, USA.
J Immunol. 1999 Feb 15;162(4):2251-8.
Tumor-specific TCR can serve as an effective target for active immunotherapy of T cell malignancies. Using the murine T cell tumor model C6VL, vaccination with C6VL TCR protected mice from a subsequent lethal dose of tumor cells. This study characterizes the immune mechanisms involved in the tumor protection, and the influence of immunologic adjuvants in inducing a protective immune response. Immune responses induced by TCR vaccines formulated with various adjuvants: QS-21, IL-12, SAF-1, CD40L, and GM-CSF were compared. QS-21, IL-12, and SAF-1 biased the humoral immune response toward Th1-type, reflected by the induction of IgG2a and IgG2b anti-C6VL TCR Abs. CD40L and GM-CSF exclusively produced IgG1 Abs, reflecting a Th2-type immune response. In our tumor model system, only vaccines containing adjuvants that induced a Th1-type immune response favored tumor protection. Furthermore, we demonstrated that CD8+ T cells were necessary and sufficient for tumor protection using anti-CD8 mAb depletion and adoptive cell transfer experiments. Transfer of hyperimmune serum containing anti-C6VL TCR Abs into na ive mice had modest anti-tumor effects and was not sufficient to prevent tumor growth. TCR-vaccinated B cell-deficient mice were not protected against C6VL tumor, and tumor protection was not completely restored after hyperimmune serum transfer. Thus, B cells may serve as important APCs in inducing a protective immune response. Based on these results future TCR vaccines should be designed to maintain native TCR conformation, as well as induce a strong Th1-type immune response.
肿瘤特异性T细胞受体可作为T细胞恶性肿瘤主动免疫治疗的有效靶点。利用小鼠T细胞肿瘤模型C6VL，用C6VL T细胞受体进行疫苗接种可保护小鼠免受后续致死剂量肿瘤细胞的侵害。本研究对肿瘤保护所涉及的免疫机制以及免疫佐剂在诱导保护性免疫反应中的影响进行了表征。比较了用各种佐剂（QS-21、白细胞介素-12、SAF-1、CD40L和粒细胞巨噬细胞集落刺激因子）配制的T细胞受体疫苗诱导的免疫反应。QS-21、白细胞介素-12和SAF-1使体液免疫反应偏向Th1型，这通过诱导IgG2a和IgG2b抗C6VL T细胞受体抗体得以体现。CD40L和粒细胞巨噬细胞集落刺激因子仅产生IgG1抗体，反映出Th2型免疫反应。在我们的肿瘤模型系统中，只有含有诱导Th1型免疫反应佐剂的疫苗有利于肿瘤保护。此外，我们通过抗CD8单克隆抗体耗竭和过继性细胞转移实验证明，CD8+T细胞对于肿瘤保护是必要且充分的。将含有抗C6VL T细胞受体抗体的超免疫血清转移到未免疫的小鼠体内具有适度的抗肿瘤作用，但不足以阻止肿瘤生长。接种T细胞受体疫苗的B细胞缺陷小鼠不能抵御C6VL肿瘤，超免疫血清转移后肿瘤保护也未完全恢复。因此，B细胞可能作为重要的抗原呈递细胞诱导保护性免疫反应。基于这些结果，未来的T细胞受体疫苗应设计成既能维持天然T细胞受体构象，又能诱导强烈的Th1型免疫反应。
