Chimeric Amino Acid Rearrangements as Immune Targets in Prostate Cancer

Abstract : Progression to metastatic castrate resistant prostate cancer (mCRPC) is a significant clinical problem. Although new hormones therapies have shown efficacy they have been largely ineffective in treating mCRPC. It is becoming increasingly clear the immune system plays a key role in long-term outcomes of cancer. Some emerging immunotherapies have been highly effective at treating late stage cancers. However, it is crucial that the immune system recognize cancer-specific or cancer-associated targets. One such target is mutations in tumors that give rise to so-called neoantigens. Some neoantigens can be shared across patients while others are unique. Despite large genomic sequencing efforts in prostate cancer, a comprehensive analysis of immunological targets has been lacking. Here we describe a first-in-principle approach to uncover the immunogenic potential of a specific type of mutation called gene rearrangements. These mutations occur when two unrelated genes fused together, creating a new gene product that may have distinct neoplastic functions. Using integrated transcriptome analysis, we have identified gene fusions with high-confidence predicted MHC class I restricted epitopes in 6 out of 50 patient tumors. One recurrent gene fusion encoded by the TMPRSS2:ERG type VI fusion was detected in 3 patients and contained a predicted HLA*02:01 restricted epitope. In vitro, we identified T cells from healthy donor peripheral blood that recognizes peptides specific for this mutation. Collectively, our data show that prostate tumors harbor targetable neoantigens encoded by gene rearrangements at a low frequency.