Defensins and Antitumor Immunity

Defensins are well-known for their antimicrobial activity, yet are also able to induce antitumor immunity when fused with non-immunogenic tumor antigens.1 They were originally isolated from human and rabbit neutrophils2,3 but have also been characterized from insects,4 plants,5 and various other vertebrates.6-9 Defensins play an important role in innate immunity against microbial infections10 and are also proposed to play roles in inflammation, wound repair, expression of cytokines and chemokines, production of histamine,11 and enhancement of antibody responses.12 The 28-42 amino acid cationic peptides10 contain six to eight highly conserved cysteine residues which form three to four pairs of intramolecular disulfide bonds.13 Vertebrate defensins are classified as alpha, beta, or gamma, based on their cellular origin and number and pattern of disulfide bridges.13 Similar in tertiary structure, alpha- and beta-defensins contain triple stranded antiparallel beta sheets.14,15 More than 50 mammalian defensins have been identified.13 In the mouse, Paneth cells and skin produce at least 17 alpha-defensins,16,17 while various epithelial cells and keratinocytes generate four beta-defensins.18-21 Six alpha-defensins and three beta-defensins have been characterized in humans.13 One of the most promising human cancer vaccine approaches is based on active immunotherapy by targeting malignant B cell expression of idiotypic antigen (Id).22 Despite reports in mice that fusion of defensins and cytokines to non-immunogenic lymphoma Id or its unique single-chain Fv fragment (sFv) renders them immunogenic, no single approach materialized to induce both humoral and T cell immunities upon delivery of tumor antigens to antigen presenting cells.23-25 In a recent study, however, protective humoral and cellular antitumor immunity was elicited against two B cell lymphomas, 38C13 and A20.1 This study demonstrates that immunization with plasmid DNA constructs containing non-immunogenic sFv fused to murine beta-defensin 2, or inflammatory chemokines such as MIP-1 alpha, accomplishes this feat (see figure 1). Potent tumor protection is induced against both the more aggressive 38C13 tumor, which requires both humoral and cellular immune responses for rejection, and the slower growing A20 lymphoma, in which only cellular immunity is protective. This is possible because beta-defensin 2 and MIP-1 alpha target immature dendritic cells (DC) by binding receptors preferentially expressed on them, such as CCR6. The result is an increase in antigen uptake, processing and presentation of nonimmunogenic antigen, inducing a humoral immune response. Induction of cellular immunity presumably occurs through an increase in expression of Th1 vs. Th2 stimulatory cytokines and chemokines that differentially chemoattract Th1 or Th2 cells. This data suggests that fusion constructs with molecules such as beta-defensin 2 or MIP-3 alpha, which target immature DC, can render a nonimmunogenic tumor antigen immunogenic and elicit protective and therapeutic antitumor immunity. Thus, similar fusion proteins might provide a general strategy for easier and more effective cancer vaccine development.

Figure 1
Figure 1. A fusion construct containing beta-defensin 2 targets CCR6-expressing immature DC and can render a non-immunogenic tumor antigen immunogenic, thus eliciting protective and therapeutic antitumor immunity.

References

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