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功效。本研究的目的是评估重组IFN-α与痘病毒疫苗结合靶向人癌胚抗原（CEA）在结肠直肠癌和胰腺腺癌的小鼠模型中的有效性和相容性，其中CEA是自身抗原。在无肿瘤小鼠的引流腹股沟淋巴结中评价IFN-α的表型和功能作用。我们研究了IFN-α给药部位（局部与远端）对痘病毒疫苗接种的抗原特异性免疫应答的影响。进行机制研究以评估IFN-α和CEA定向的痘病毒疫苗在荷瘤CEA转基因小鼠中的功效。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扩张，并改善细胞毒性（自然杀伤细胞和CD 8+）和抗原呈递。通过在接种部位远端给予IFN-α避免了对牛痘病毒的抑制。IFN-α和疫苗的组合抑制肿瘤生长，提高存活率，并在患有CEA+腺癌的小鼠中引起CEA特异性CTL应答。在患有胰腺肿瘤的小鼠中，IFN-α减缓肿瘤生长，诱导CTL活性，并增加CD 8+肿瘤浸润淋巴细胞。这些数据表明，IFN-α可用作抗原导向痘病毒疫苗的生物应答调节剂，以产生显著的治疗性抗肿瘤免疫应答。这项研究提供了基本原理和机制的见解，以支持这种免疫策略在CEA表达癌患者中的临床试验。

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.