Endogenous viral elements constitute a complementary source of antigens for personalized cancer vaccines

Area of Science:

• Immunology
• Oncology
• Bioinformatics

Background:

• Current personalized cancer vaccines (PCVs) primarily rely on neoantigens from somatic mutations, limiting efficacy in low tumor mutational burden (TMB) cancers.
• There is a critical need for alternative tumor antigens to broaden the applicability of PCVs to a wider patient population, including those with low TMB.
• Endogenous retroviral elements (EVEs) represent a largely untapped source of tumor-associated antigens.

Purpose of the Study:

• To investigate the potential of endogenous retroviral elements (EVEs) as tumor antigens for personalized cancer vaccine development.
• To develop and validate a computational pipeline for predicting EVE-derived epitopes with therapeutic potential.
• To assess the immunogenicity and therapeutic efficacy of EVE-based vaccine strategies in preclinical models.

Main Methods:

• Large-scale genomic analyses of EVE expression in healthy tissues and various solid cancers.
• Correlation analysis between EVE expression breadth and clinical outcomes (overall survival, progression-free survival) in melanoma patients treated with checkpoint inhibitors.
• Development of the ObsERV computational pipeline for predicting EVE-derived epitopes presented on tumors.
• Preclinical testing of EVE-based vaccine strategies to evaluate T-cell responses and tumor protection.

Main Results:

• Genomic analyses confirmed EVEs as prevalent tumor antigens across multiple cancer types.
• The breadth of EVE expression in tumors significantly stratified melanoma patients, predicting differential responses to checkpoint inhibitor therapy.
• The ObsERV pipeline successfully predicted EVE-derived peptides presented as epitopes on tumors.
• Preclinical studies demonstrated that EVE-based vaccines induced robust, poly-functional CD4+ and CD8+ T-cell responses and provided long-term tumor protection.

Conclusions:

• Endogenous retroviral elements (EVEs) represent a viable and promising source of tumor antigens for personalized cancer vaccines.
• The ObsERV computational pipeline provides a valuable tool for identifying and designing EVE-based vaccine candidates.
• EVE-targeting personalized cancer vaccines hold significant potential to improve therapeutic outcomes, particularly for patients with low tumor mutational burden (TMB) cancers.