Abstract 1564: Partial immunovesiculectomy by Th-1 dendritic cell vaccination: Implications for immunotherapy of solid tumors

Abstract

Abstract The efficient and specific manner by which the mammalian immune system identifies and eradicates target antigen has stood as a testament to both its power and potential to similarly eradicate neoplastic self. In spite of this undeniable potential, the recalcitrance of the immune system to directed manipulation has been formidable, and the manner by which self-directed cellular (Th-1) immunity might be reproducibly promulgated has not yet been elucidated. Recent basic advances in the understanding of dendritic cell (DC) maturation, Th-1 polarization, T-cell homing, and plasmacytoid DC biology might allow promulgation of self-directed cellular immunity provided that all important aspects of such promulgation have been identified and are properly implemented. To investigate this hypothesis, seminal vesicle (SV), was chosen as a model organ system in the wild type mouse. In this system, SV serves as a proxy tumor from an immunological perspective: antigenically distinguishable from other organ systems yet comprised entirely of self tissue antigens and stringently protected from immunological recognition by mechanisms of central and peripheral tolerance. Equivalent class I and class II antigenic environments were provided to spleen-derived DC by electroporation with SV mRNA and incubation with SV lysate. DC were matured with a full complement of inflammatory cytokines. DC were applied i.p. in the vicinity of the SV so as to have access to the specific lymphatics that drain the area. Plasmacytoid recruitment and IFN-γ secretion was induced by local i.p. administration of particulate imiquimod. Two months post-vaccination, SV and other organs were harvested and examined for pathological changes by H&E staining. Ipsilateral SV was reduced in size as much as 75% in comparison to contralateral SV. Active inflammatory responses were ongoing as evidenced by mixed lineage inflammatory infiltrates comprising lymphocytes, neutrophils, eosinophils, macrophages, and multinucleated giant cells. Remnant SV physiologic structures were infiltrated by fibrous connective tissue and scar. Antigen-specific tissue destruction was shown to be dependent upon local TLR-7 adjuvantation with imiquimod as well as the activation of lymphocyte subsets. Antigenically similar tissues demonstrated normal histopathology. Subsequent experiments using the TRAMP-C2 prostate cancer cell line demonstrated the ability of Th-1 DC vaccination to recognize and eradicate neoplastic self as demonstrated by Kaplan-Meier survival analysis. The data demonstrate that provision and maintenance of the appropriate signals are sufficient to mediate durable self-directed Th-1 immunity against peripheral-self. The data further suggest a plausible role for DC vaccination as a front line therapy for the treatment of some neoplasias in the future. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1564. doi:1538-7445.AM2012-1564