Peptide Modification Diminishes HLA Class II-restricted CD4⁺ T Cell Recognition of Prostate Cancer Cells

Prostate cancer poses an ongoing problem in the western world accounting for significant morbidity and mortality in the male population. Current therapy options are effective in treating most prostate cancer patients, but a significant number of patients progress beyond a manageable disease. For these patients, immunotherapy has emerged as a real option in the treatment of the late-stage metastatic disease. Unfortunately, even the most successful immunotherapy strategies have only led to a four-month increase in survival. One issue responsible for the shortcomings in cancer immunotherapy is the inability to stimulate helper CD4⁺ T cells via the HLA class II pathway to generate a potent antitumor response. Obstacles to proper HLA class II stimulation in prostate cancer vaccine design include the lack of detectable class II proteins in prostate tumors and the absence of defined class II specific prostate tumor antigens. Here, for the first time, we show that the insertion of a lysosomal thiol reductase (GILT) into prostate cancer cells directly enhances HLA class II antigen processing and results in increased CD4⁺ T cell activation by prostate cancer cells. We also show that GILT insertion does not alter the expression of prostate-specific membrane antigen (PSMA), an important target in prostate cancer vaccine strategies. Our study suggests that GILT expression enhances the presentation of the immunodominant PSMA₄₅₉ epitope via the HLA class II pathway. Biochemical analysis showed that the PSMA₄₅₉ peptide was cysteinylated under a normal physiologic concentration of cystine, and this cysteinylated form of PSMA₄₅₉ inhibited T cell activation. Taken together, these results suggest that GILT has the potential to increase HLA class II Ag presentation and CD4⁺ T cell recognition of prostate cancer cells, and GILT-expressing prostate cancer cells could be used in designing cell therapy and/or vaccines against prostate cancer.