The connection of innate and adaptive anti-cancer immunity

ifn - α是一种多效性细胞因子，具有免疫调节特性，可提高治疗性癌症疫苗的疗效。本研究的目的是评估重组ifn - α与针对人癌胚抗原（CEA）的痘病毒疫苗在小鼠结直肠癌和胰腺腺癌模型中的有效性和相容性，其中CEA是一种自身抗原。研究了ifn - α在无肿瘤小鼠腹股沟引流淋巴结中的表型和功能影响。我们研究了ifn - α给药部位（局部或远端）对痘病毒疫苗抗原特异性免疫反应的影响。机制研究评估了ifn - α和CEA导向痘病毒疫苗对荷瘤CEA转基因小鼠的疗效。我们确定了ifn - α的剂量和时间表，诱导引流腹股沟淋巴结的局部区域扩张，改善细胞毒性（自然杀手和CD8+）和抗原呈递。通过在接种部位远端施用ifn - α，可以避免牛痘病毒的抑制。在CEA+腺癌小鼠中，ifn - α和疫苗联合抑制肿瘤生长，提高生存率，并引发CEA特异性CTL反应。在胰腺肿瘤小鼠中，ifn - α减缓肿瘤生长，诱导CTL活性，增加CD8+肿瘤浸润淋巴细胞。这些数据表明，ifn - α可以作为抗原导向痘病毒疫苗的生物反应修饰剂，产生显著的治疗性抗肿瘤免疫反应。这项研究为支持这种免疫治疗策略在cea表达癌患者中的临床试验提供了理论基础和机制见解。

IFN-alpha is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-alpha with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen. The phenotypic and functional effects of IFN-alpha were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-alpha administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-alpha and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice. We identified a dose and schedule of IFN-alpha that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8+) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-alpha distal to the site of vaccination. The combination of IFN-alpha and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA+ adenocarcinomas. In mice with pancreatic tumors, IFN-alpha slowed tumor growth, induced CTL activity, and increased CD8+ tumor-infiltrating lymphocytes. These data suggest that IFN-alpha can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.