Vaccine therapy for cutaneous T-cell lymphoma

It has generally been acknowledged that cytotoxic T lymphocytes (CTLs) play a potent role in the eradication of tumor cells. They discriminate malignant cells from normal cells by recognizing peptide fragments of tumor-associated proteins in a major histocompatibility complex (MHC) class I molecule-restricted manner [ 1,2]. Complicated processes in CTL activation/maturation are induced by dendritic cells (DCs) that bear tumor-associated antigen as follows. (1) Immature DCs that neighbor tumor lesions are changed to the mature form by phagocytically incorporating necrotic tumor proteins and by reacting with local cytokines [3]. The mature DCs exhibit upregulated expression of MHC and costimulatory molecules. (2) Tumor-associated antigen-expressing DCs migrate in secondary lymph nodes and encounter a naive form of CD8(+) T cells [4]. The DC activation is completed in secondary lymphoid organs while cross-talking with CD40 ligand- and receptor activator of NF-kappaB (RANK) ligand-expressing T cells [5]. (3) Naive CD8(+) T cells differentiate into memory/effector CTLs after intimate contact with antigen-expressing DCs; this is termed "antigen-specific priming" [6]. (4) Memory/ effector forms of tumor-specific CTLs circulate systemically and migrate in tumor lesions and participate in cytolysis of tumor cells [7]. Thus, DCs that bear tumor-associated antigen trigger the effective generation of tumoricidal immunity. Animal model studies showed a potential for DC-based tumor immunotherapy to elicit protective antitumor immune responses; the validity of such an approach was confirmed in humans [8,9]. Although the understanding of the differentiation process of DCs under the influence of cytokines and growth factors progressed at a rapid pace [10], the intricate manipulations that are required for in vitro preparation of large numbers of DCs in a form that are appropriate for immunotherapy is a major obstacle in current inummotherapeutic strategies. We reported that disruption of the corneum barrier resulted in enhanced permeability and alterations in the immunoregulatory function of the skin in such a way that epidermal Langerhans cells (LCs) function as vigorous antigen presenters for T helper (Th) cells and CTLs [11, 12]. Various studies showed that LCs target tumor antigens for induction of antitumor CTL responses in vivo and in vitro [13,14]. Topical application of tumor-associated peptide onto the stratum corneum barrier-disrupted skin in mice induced tumoricidal immune responses in vivo and in vitro [11]. LCs with upregulated expression of MHC molecules and costimulatory molecules seem to be responsible for increasing the frequency of CTL precursors. Cutaneous T-cell lymphoma (CTCL) is the most common malignancy of mature T cells, and is a neoplastic amplification of cutaneous T cells, which are normally a major subset of recirculating T cells with distinctive differentiation markers (CD4, CD45RO, and cutaneous lymphocyte-associated antigen). CD7, a marker of mature T cells, is not expressed on CTCL cells in almost all cases [15]. Mycosis fungoides (MF) and its leukemic variant, Sezary syndrome (SzS), are the most frequent types of CTCL. Despite efforts during the past year to identify CTL epitope peptides of tumor cells, only one epitope has been isolated and identified from CTCL cells as a peptide fragment of clonotypic T-cell receptor (TCR) [16]. A percutaneous peptide immunization strategy that was developed in our group operates well in a mouse model, which suggests its efficacy in treatment of CTCLs with identified epitope peptides.