LC-MSMS of primary HGSC class I immunopeptidom

High-grade serous ovarian cancer (HGSC), the principal cause of death from gynecological malignancies in the world, has not significantly benefited from recent progress in cancer immunotherapy. While HGSC infiltration by lymphocytes correlates with superior survival, the nature of antigens that can elicit anti-HGSC immune responses is unknown. The goal of this study was to establish the global landscape of HGSC tumor-specific antigens (TSAs) using a mass spectrometry pipeline that interrogates all reading frames of all genomic regions. In 23 HGSC tumors, we identified 113 TSAs. Classic TSA discovery approaches focusing only on mutated exonic sequences would have uncovered only seven of these TSAs. Other mutated TSAs resulted from out-of-frame exonic translation or from non-exonic sequences. The most interesting group of TSAs (n = 94) derived from aberrantly expressed unmutated genomic sequences which are not expressed in normal tissues. These aberrantly expressed TSAs (aeTSAs) derived primarily from non-exonic sequences, in particular intronic (31%) and intergenic (22%). Their expression was regulated at the transcriptional level by variations in gene copy number and DNA methylation. While mutated TSAs were unique to individual tumors, aeTSAs were shared by a large proportion of HGSCs. We conclude that, in view of their number and the fact that they are shared by many tumors, aeTSAs may be the most attractive targets for HGSC immunotherapy.