Efficient processing of target antigens by the ubiquitin-proteasome-system
(UPS) is essential for treatment of cancers by T cell therapies. However,
immune escape due to altered expression of IFN-γ-inducible components of the
antigen presentation machinery and consequent inefficient processing of HLA-
dependent tumor epitopes can be one important reason for failure of such
therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor
antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic
T lymphocytes (CTL) led to resistance against CTL-induced lysis because of
impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation
of p97/VCP expression, which is an IFN-γ-independent component of the UPS and
part of the ER-dependent protein degradation pathway (ERAD), was found to be
essentially involved in the observed immune escape. In support, our data
demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant
melanoma cells completely restored immune recognition by Melan-A/MART-126-35
CTL. In conclusion, our experiments show that impaired expression of
IFN-γ-independent components of the UPS can exert rapid immune evasion of
tumor cells and suggest that tumor antigens processed by distinct UPS
degradation pathways should be simultaneously targeted in T cell therapies to
restrict the likelihood of immune evasion due to impaired antigen processing
