Beyond Canonical Neoantigens: Emerging Technologies for Identification of Noncanonical Antigens and Implications for Personalized Cancer Vaccines

Abstract

Simple Summary Cancer cells often produce proteins not found in healthy cells. Personalized cancer vaccines (PCV) are designed to train the patient’s immune system to recognize these unique proteins and attack cancer cells while sparing normal tissues. Currently, PCV targets are usually derived from genetic mutations in a patient’s tumor identified on sequencing. However, growing evidence suggests that many cancer-specific proteins actually arise from aberrant processes in transcription and translation, even in the absence of DNA mutations. Compared to mutation-derived proteins, these proteins are often more structurally distinct and can be especially effective at triggering immune responses. New technologies, such as long-read DNA/RNA sequencing, circular RNA sequencing, ribosome profiling, and mass spectrometry, have made it possible to identify previously hidden cancer-specific proteins. In this review, we describe the diverse sources and identification technologies of aberrant cancer-associated proteins beyond genetic mutations and highlight their clinical relevance in next-generation PCVs.