Grant Julieann F, Iwasawa Toshihisa, Sinn Haley W, Siemens D Robert, Griffith Thomas S, Takacs Elizabeth B, Ratliff Timothy L
Medical Scientist Training Program, University of Iowa, Iowa City, IA 52242-1089, USA.
Int J Cancer. 2006 Dec 1;119(11):2632-41. doi: 10.1002/ijc.22220.
Human prostate cancers characteristically express low levels of major histocompatibility complex (MHC) Class I, which makes it challenging to induce protective antitumor responses involving T cells. Here we demonstrate that a whole cell tumor vaccine can induce protective T cell immunity to a low MHC Class I-expressing mouse prostate cancer cell line, RM-1. ALVAC recombinant canarypox viruses encoding interleukin-2, interleukin-12 and tumor necrosis factor-alpha were used to create therapeutic vaccines in 2 different ways. The RM-1 cells were pre-infected in vitro with the viruses prior to injection (pre-infection vaccine) or the RM-1 cells were injected alone, followed by the viruses (separate injection vaccine). The vaccines were each tested subcutaneously or intradermally. The pre-infection vaccine resulted in 100% clearance of primary tumors, whereas intradermal delivery of the separate injection vaccine cleared 40-60% of primary tumors. Despite the highly efficient primary tumor clearance by the pre-infection vaccine, only the separate injection vaccine generated protection upon rechallenge. Tumor-free survival induced by the separate injection vaccine required natural killer (NK) cells, CD4(+), and CD8(+) T cells. None of these cells alone were sufficient to induce tumor-free survival to the primary challenge, demonstrating an important cooperativity between NK cells and T cells. Secondary clearance of tumors also required NK and CD8(+) T cells, but not CD4(+) T cells. We report for the first time the generation of T cell immunity to the RM-1 prostate cancer cell line, demonstrating that it is possible to generate protective T cell immunity to a MHC I-low expressing tumor.
人类前列腺癌的特征是主要组织相容性复合体（MHC）I类分子表达水平较低，这使得诱导涉及T细胞的保护性抗肿瘤反应具有挑战性。在此，我们证明了一种全细胞肿瘤疫苗可以诱导对低表达MHC I类分子的小鼠前列腺癌细胞系RM-1产生保护性T细胞免疫。编码白细胞介素-2、白细胞介素-12和肿瘤坏死因子-α的ALVAC重组金丝雀痘病毒被用于以两种不同方式制备治疗性疫苗。RM-1细胞在注射前先在体外被病毒预感染（预感染疫苗），或者单独注射RM-1细胞，随后再注射病毒（分开注射疫苗）。每种疫苗都通过皮下或皮内途径进行测试。预感染疫苗导致原发肿瘤100%清除，而皮内注射分开注射疫苗清除了40%-60%的原发肿瘤。尽管预感染疫苗对原发肿瘤的清除效率很高，但只有分开注射疫苗在再次攻击时产生了保护作用。分开注射疫苗诱导的无瘤生存需要自然杀伤（NK）细胞、CD4(+)和CD8(+) T细胞。这些细胞单独一种都不足以诱导对初次攻击的无瘤生存，这表明NK细胞和T细胞之间存在重要的协同作用。肿瘤的二次清除也需要NK和CD8(+) T细胞，但不需要CD4(+) T细胞。我们首次报道了对RM-1前列腺癌细胞系产生T细胞免疫，证明了有可能对低表达MHC I类分子的肿瘤产生保护性T细胞免疫。
