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.
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