A MULTIPEPTIDE VACCINE IN MELANOMA PATIENTS WITH EVALUATION OF INJECTION SITE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 癌症疫苗有望成为一种低毒的治疗方法，可以利用免疫系统对癌症，特别是黑色素瘤的反应。黑色素瘤疫苗可以在许多或大多数患者中诱导免疫反应，但临床效果一直令人失望。理解皮肤接种免疫生物学的经典范例是，与佐剂一起运送的抗原会产生炎症刺激，进而诱导表皮朗格汉斯细胞成熟并迁移到引流淋巴结。然而，在佐剂中重复接种黑色素瘤多肽与戏剧性的慢性局部炎症有关，并且可能具有不同的生物学特性。自身免疫性和感染性疾病的慢性炎症可导致非典型淋巴区域的新淋巴组织。这一过程被称为“淋巴新生”，可导致第三淋巴器官(TLO)的功能类似于淋巴。在单次注射不完全弗氏佐剂和GM-CSF乳剂后，我们观察到人皮肤真皮中的淋巴结样聚集体(LNLA)。这些LNLA含有成熟的CD83 DC-LAMP树突状细胞、T细胞、B细胞和外周结节地址蛋白(PNAD)表达的微血管，提示高内皮微静脉。对反复接种佐剂的多肽疫苗部位的初步研究表明，淋巴新生的其他特征，但也有证据表明，聚集体中有调节细胞。在目前的建议中，我们建议通过将具有良好特性的多肽疫苗免疫与从复制免疫部位获得的组织的广泛研究相结合，来定义人类黑色素瘤免疫微环境中的细胞和分子事件。最重要的假设是，这些疫苗部位的免疫反应是通过淋巴样新生和TLO介导的，随着这些过程和相关调控过程的阐明，我们预计能够发现提高疫苗效力的机会。这项工作的结果可能会改变我们对免疫微环境中免疫生物学的理解，并确定联合治疗以提高抗肿瘤免疫的方法。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cancer vaccines hold promise as a low toxicity treatment that may harness the immune system's response to cancer, and to melanoma in particular. Melanoma vaccines can induce immune responses in many or most patients, but the clinical impact has been disappointing. The classic paradigm for understanding the immunobiology of cutaneous vaccination is that antigen delivered with an adjuvant creates an inflammatory stimulus, which in turn induces epidermal Langerhans cells to mature and to migrate to draining lymph nodes. However, repeat vaccination with melanoma peptides in adjuvant is associated with dramatic chronic local inflammation and may have different biology. Chronic inflammation in autoimmune and infectious diseases can lead to new lymphoid tissues in locations that are not classic lymphoid areas. This process, termed "lymphoid neogenesis," can result in tertiary lymphoid organs (TLO) that function like lymph nodes. We have observed lymph node-like aggregates (LNLA) in the dermis of human skin after a single injection of an emulsion of incomplete Freund's adjuvant plus GM-CSF. These LNLA contain mature CD83+DC-LAMP+ dendritic cells, T cells, B cells, and peripheral node addressin (PNAd) expressing microvessels suggestive of high endothelial venules. Preliminary studies in sites of repeated peptide vaccination with adjuvant show other features of lymphoid neogenesis, but there also is evidence of regulatory cells in the aggregates. For the current proposal, we propose to define the cellular and molecular events in the immunization microenvironment in humans with melanoma by combining immunization with a well-characterized multipeptide vaccine with extensive studies of tissue obtained from a replicate immunization site. The overarching hypothesis is that the immune response at these vaccine sites is mediated through lymphoid neogenesis and TLOs, and we anticipate being able to identify opportunities for improving vaccine efficacy as these processes and associated regulatory processes are elucidated. The results of this work will likely change our understanding of the immunobiology in the immunization microenvironment and identify approaches for combination therapies to improve antitumor immunity.