The connection of innate and adaptive anti-cancer immunity

使用重组鸡痘病毒靶向递送鼠干扰素（IFN）-γ： 自然杀伤（NK）细胞募集到局部淋巴结和引发肿瘤特异性 宿主免疫IFN-γ是一种促炎细胞因子， 免疫调节剂。在本研究中，复制缺陷型重组禽（鸡痘） 将病毒工程化以表达鼠IFN-γ基因（rF-MuIFN-γ），其基本原理是 将浓缩水平的细胞因子输送到局部组织微环境。 皮下（s.c.）rF-MuIFN-γ给药导致IFN-γ产生， 局限于注射部位的组织微环境，以及（2）在生物学上 活性，如I类主要组织相容性复合物的显著增加所证明 (MHC)皮下表达水平在rF-MuIFN-γ施用后生长的肿瘤。 用rF-MuIFN-γ感染高度致瘤性鼠细胞系MC 38， 有效的基于肿瘤细胞的疫苗，通过保护小鼠免于形成原发性肿瘤， 随后的肿瘤挑战。细胞疫苗是完全无效的， 用用rIFN-γ预处理的MC 38细胞或用 野生型鸡痘病毒（FP-WT）。局部引流淋巴结的临床分析 注射基于rF-MuIFN-γ的肿瘤细胞疫苗揭示了 肿瘤特异性细胞裂解（CTL）以及针对肿瘤细胞的大量裂解， NK敏感的YAC-1细胞。流式细胞术分析结合功能测定证实了 引流淋巴结内持续存在NK1.1（+）细胞长达5天 注射rF-MuIFN-γ后。在给药前用NK细胞耗竭抗体处理的小鼠 注射rF-MuIFN-γ感染的MC 38肿瘤细胞不能保护其免于原发性免疫缺陷。 肿瘤生长; NK耗竭小鼠中注射部位引流淋巴结的分析 揭示了伴随的肿瘤特异性CTL活性的丧失。这些发现提供 NK细胞对宿主先天免疫的贡献也提供了证据， 免疫调节信号的发展所需的适应性免疫反应，其中， 反过来，保护接种疫苗的小鼠免受肿瘤生长的影响。

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.