The connection of innate and adaptive anti-cancer immunity

使用重组鸡痘病毒靶向传递小鼠干扰素-γ：自然杀伤(NK)细胞在区域淋巴结中的募集和肿瘤特异性宿主免疫的启动。干扰素是一种促炎细胞因子，也是一种有效的免疫调节剂。在这项研究中，一种复制缺陷的重组禽类(鸡痘)病毒被设计成表达小鼠干扰素-γ基因(RF-Mu干扰素-γ)，其原理是将细胞因子的集中水平输送到局部组织微环境中。皮下(S.C.)给药后，干扰素-γ的产生仅限于注射部位的组织微环境，(2)具有生物活性，主要组织相容性复合体(MHC)在S.C.的表达水平显著增加。射频-干扰素-伽玛刀治疗后肿瘤生长。用RF-MuIFN-γ感染高致瘤性小鼠细胞系MC38，可以作为一种有效的肿瘤细胞疫苗，保护小鼠免受原发肿瘤的形成和后续的肿瘤攻击。如果用MC38细胞接种小鼠，无论是经过rIFN-γ预处理的MC38细胞还是感染野生型鸡痘病毒(FP-WT)的小鼠，基于细胞的疫苗都是完全无效的。对注射RF-MuIFN-γ的肿瘤细胞疫苗注射部位的区域淋巴结的分析显示，存在肿瘤特异性细胞裂解(CTL)以及大量针对NK敏感的YAC-1细胞的裂解。流式细胞仪分析结合功能分析证实，在注射RF-MuIFN-Gamma后，NK1.1(+)细胞在这些引流淋巴结内持续存在长达5天。在注射感染了RF-MuIFN-Gamma的MC38肿瘤细胞之前，用NK细胞耗尽抗体治疗的小鼠并没有受到原发肿瘤生长的保护；对NK耗竭小鼠注射部位的淋巴引流的分析显示，伴随着肿瘤特异性CTL活性的丧失。这些发现提供的证据表明，NK细胞也提供了发展适应性免疫反应所需的免疫调节信号，这反过来又保护了接种疫苗的小鼠免受肿瘤生长。NK细胞以其对宿主天然免疫的贡献而闻名。

Targeted delivery of murine interferon (IFN)-gamma using a recombinant fowlpox virus: natural killer (NK) cell recruitment to regional lymph nodes and priming of tumor-specific host immunity. IFN-gamma is a proinflammatory cytokine that also acts as a potent immunomodulatory agent. In this study, a replication-deficient recombinant avian (fowlpox) virus was engineered to express the murine IFN-gamma gene (rF-MuIFN-gamma) with the rationale of delivering concentrated levels of the cytokine to a local tissue microenvironment. Subcutaneous (s.c.) rF-MuIFN-gamma administration resulted in IFN-gamma production that was restricted to the tissue microenvironment of the injection site and (2) was biologically active, as evidenced by a significant increase of class I major histocompatibility complex (MHC) expression levels in s.c. growing tumors following rF-MuIFN-gamma administration. Infection of a highly tumorigenic murine cell line, MC38, with rF-MuIFN-gamma functioned as an effective tumor cell-based vaccine by protecting mice from the formation of primary tumors and from subsequent tumor challenge. The cell-based vaccine was completely ineffective if mice were vaccinated with MC38 cells either pretreated with rIFN-gamma or infected with the wild-type fowlpox virus (FP-WT). Analysis of the regional lymph nodes draining the site of injection of the rF-MuIFN-gamma-based tumor cell vaccine revealed the presence of tumor-specific cell lysis (CTL) as well as a significant amount of lysis directed at NK-sensitive YAC-1 cells. Flow cytometric analyses coupled with functional assays confirmed the sustained presence of NK1.1(+) cells within those draining lymph nodes for up to 5 days after rF-MuIFN-gamma injection. Mice treated with NK cell-depleting antibodies prior to the injection of the rF-MuIFN-gamma-infected MC38 tumor cells were not protected from primary tumor growth; analysis of the lymph nodes draining the injection site in NK-depleted mice revealed an accompanying loss of the tumor-specific CTL activity. The findings provide evidence that NK cells, known for their contributions to host innate immunity, also provide immunoregulatory signals required for the development of an adaptive immune response, which, in turn, protected vaccinated mice against tumor growth.