Antibody-Targeted NY-ESO-1 to Mannose Receptor or DEC-205 In Vitro Elicits Dual Human CD8+ and CD4+ T Cell Responses with Broad Antigen Specificity

Abstract

Immunization of cancer patients with vaccines containing full-length tumor Ags aims to elicit specific Abs and both CD4+ and CD8+ T cells. Vaccination with protein Ags, however, often elicits only CD4+ T cell responses without inducing Ag-specific CD8+ T cells, as exogenous protein is primarily presented to CD4+ T cells. Recent data revealed that Ab-mediated targeting of protein Ags to cell surface receptors on dendritic cells could enhance the induction of both CD4+ and CD8+ T cells. We investigated in this study if these observations were applicable to NY-ESO-1, a cancer-testis Ag widely used in clinical cancer vaccine trials. We generated two novel targeting proteins consisting of the full-length NY-ESO-1 fused to the C terminus of two human mAbs against the human mannose receptor and DEC-205, both internalizing molecules expressed on APC. These targeting proteins were evaluated for their ability to activate NY-ESO-1–specific human CD4+ and CD8+ T cells in vitro. Both targeted NY-ESO-1 proteins rapidly bound to their respective targets on APC. Whereas nontargeted and Ab-targeted NY-ESO-1 proteins similarly activated CD4+ T cells, cross-presentation to CD8+ T cells was only efficiently induced by targeted NY-ESO-1. In addition, both mannose receptor and DEC-205 targeting elicited specific CD4+ and CD8+ T cells from PBLs of cancer patients. Receptor-specific delivery of NY-ESO-1 to APC appears to be a promising vaccination strategy to efficiently generate integrated and broad Ag-specific immune responses against NY-ESO-1 in cancer patients.

Differential Effects of Viral Vectors on Migratory Afferent Lymph Dendritic CellsIn VitroPredict Enhanced ImmunogenicityIn Vivo

“…DEC-205 is currently the only receptor which has been visualized on most DC in the T cell area of secondary lymphoid tissues, which are the sites for the generation of immunity and tolerance in mouse models and humans (7,21). Targeting of DEC-205-expressing DC by either chimeric antigen-antibody complexes or recombinant vectors has been proposed to be an effective approach to improve immune responses (7,57). DC draining the skin were found to be FSC high DEC-205 ϩ CD11c ϩ CD8 Ϫ cells.…”

Targeting DC-SIGN via its neck region leads to prolonged antigen residence in early endosomes, delayed lysosomal degradation, and cross-presentation

“…Antigen-presenting cells that were treated with NY-ESO-1 targeted to the CLRs DEC-205 and MR presented a peptide repertoire that was distinct from cells treated with soluble protein. 36 Consequently, targeting antigens to DC-SIGN via both neck and CRD domains may provide a means to broaden the peptide repertoire that is presented to T cells.Apart from mediating pathogen binding and internalization, DC-SIGN is known to activate intracellular signal pathways on pathogen recognition. The receptor is associated with a signalosome complex consisting of the scaffold proteins LSP1, KSR1, and CNK and the kinase Raf-1.…”

Spatial separation of the processing and MHC class I loading compartments for cross-presentation of the tumor-associated antigen HER2/ neu by human dendritic cells

“…17 Other authors have demonstrated that inhibition of endosomal acidification either improved or had no effect on the cross-presentation. [47][48][49] These discrepancies indicate that endosomal acidification plays a critical role for some epitopes, but might be detrimental for others, which may relate to destruction of some epitopes by proteases active in the different test situations.…”