Tumor-specific mutations as targets for cancer immunotherapy

Abstract

The fundamental job of the immune system is to discriminate self from nonself. To achieve this, the immune system is actively tolerized against self proteins. When pathogens enter a host, they introduce foreign proteins to which the host is not tolerant, and an immune response ensues. In contrast, tumors represent a special case, as the vast majority of tumor proteins are "self" and hence do not trigger immune activation. However, mutation of genes important for regulation of cell growth is the underlying cause of cancer and any point mutation, insertion, reading frame-shift or protein fusion that generates a new protein sequence could theoretically be recognized as foreign by the immune system. With the advent of high-throughput sequencing technologies, we have entered an era where the tumor and germline genomes of individual patients can be sequenced, such that the entire repertoire of tumor-specific mutations can be known. To date, more than 78,000 somatic mutations have been reported in human cancer. While the prospect of targeting this huge diversity of mutations via pharmacological approaches appears daunting, T-cell-based treatments may offer a practical alternative owing to the enormous repertoire of antigen receptors expressed by the human T-cell compartment. To what extent are cancer mutations recognized by the immune system? To what extent can they be targeted by immunotherapy? Here, we review the work to date on these questions with a focus on tumor-specific mutations that have transitioned from basic laboratory investigations through to clinical trials in humans. Our goal is to identify the major issues that need to be resolved to enable advances in DNA sequencing to be translated to effective T-cell therapies in the clinic.