Unveiling candidate neoantigens in serous ovarian carcinoma through alternative splicing analysis
Ovarian cancer (OvCa) affects over 300,000 women worldwide and is the fifth leading cause of death in women. High-grade serous ovarian carcinoma (HGSOC) is the most common and lethal subtype of OvCa, accounting for 70%–80% of all deaths related to ovarian cancer. 80% of women diagnosed with HGSOC will relapse and treatment options are limited in part due to a lack of FDA-approved targeted therapies. Recent studies have posited that aberrant splicing leading to novel, tumor-specific protein products may be used in the diagnosis of cancer. Furthermore, these splicing-derived (sd) neopeptides could be highly immunogenic and thus be actionable neoantigens that could be leveraged as therapeutic targets. We aimed to identify HGSOC-specific splice events and predict the immunogenic binding capacity of sd-neopeptides in tumors from 40 late-stage HGSOC patients. We detected 334 HGSOC-specific aberrant splice events, with five of those events shared by at least 50% of our patient cohort. Downstream pathway analysis revealed that the predicted loss of function from these five shared aberrant AS events may lead to uncontrolled cell proliferation. We unveiled 76 novel candidate neoantigens from these five events using high confidence ranking from DeepHLApan. We will confirm their immunogenicity using T-cell proliferation assays. These novel antigens may lead to the development of advanced CAR-T cell therapies or peptide vaccines and offer novel, highly targeted therapeutic avenues to explore in OvCa.