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Factoring in Antigen Processing in Designing Antitumor T-Cell Vaccines 19
This process eliminates most potentially autoreactive T cells and is of central
importance for the development of tolerance to self-antigens, including those
expressed by tumor cells. Analyses of the T cells of b1i/LMP2 / mice indicated
a 50% reduction in the frequency of CD8 þ T cells in the periphery (147). Also,
the T-cell repertoire against several epitopes was drastically altered (52). Thus,
the processing of antigens by immunoproteasomes in the thymus shapes the
peripheral T-cell repertoire that can be mobilized by T-cell vaccines.
Impact of Processing on T-Cell Responses
It is accepted that CD8 þ T-cell priming and cross-priming are primarily mediated
by DCs. Both priming and cross-priming of CD8 þ T cells depend on the
processing of MHC class I–restricted antigens by the proteasomes of DCs (122).
DCs exist in at least two states: the immature and mature states. Immature DCs
reside in tissues, have the capacity of capturing antigens, and express both
standard and immunoproteasomes. Upon stimulation, tissue-resident DCs mature
and migrate to the draining lymph node. Mature DCs lose endocytic capacity,
upregulate co-stimulatory molecules, process antigens efficiently, and express
only immunoproteasomes. Given that some tumor-associated peptide antigens
(but not all) are produced by standard proteasomes of tumors but not by
immunoproteasomes of DCs, vaccines exploiting the recipients’ DCs to elicit
T-cell responses should primarily incorporate target antigens that are efficiently
processed by both types of proteasomes. In the context of the HLA-A2-restricted
peptide Melan-A26–35, which is inefficiently produced by immunoproteasome,
the efficacy of protein-based vaccines at eliciting specific CD8 þ T cells in
HLA-A2 transgenic mice was low (55). In contrast, the same vaccine administered
to immunoproteasome-deficient mice elicited a high frequency of specific
CD8 þ T cells. Further analyses confirmed that the in vivo anti-Melan-A T-cell
response was controlled by the proteasomal processing of DCs.
It has been shown that particular DC subsets (CD8 þ DCs) stimulate T cells
owing to their capacities of acquiring and processing exogenous antigens
(148–150). Interestingly, it was recently reported that a CD8 þ DC subset, which
stimulated efficiently CD8 þ T cells and to some extent CD4 þ T cells, contained
higher levels of several gene products involved in antigen processing (including
ERAAP, cathepsins, Gilt, AEP, and cystatins) than CD8 DCs, which stimulated
primarily CD4 þ T cells but not CD8 þ T cells (151). Differences in enzymes
involved in antigen processing have also been documented in the context of
human DCs (152). Thus, the effectiveness of protein-based antitumor T-cell
vaccines is not only influenced by the type of proteasomes expressed by the DCs
but also by the differential expression of a large variety of other processing
enzymes.
It was originally postulated that immature DCs residing at different anatomical
sites captured antigens and, upon maturation and migration to draining
lymph nodes, processed and presented them to activate antigen-specific T cells