Content area
Full Text
Although tumors with a high mutational load have been associated with a dismal prognosis, in this era of immunotherapy, mutations may provide a target for cancer-specific cytotoxic treatment and may become beneficial. Next-generation sequencing of hundreds of tumor types has revealed that many more somatic mutations occur in the DNA of cancer cells than were known previously. Many of these mutations occur in the coding regions of genes and are therefore transcribed into RNA, which is then translated into proteins. Fragments of these proteins may appear ultimately as altered peptides displayed by HLA molecules on the surface of tumor cells, where they can be recognized as “foreign” peptides — so-called neoantigens — by T cells, in much the same way that T cells sense microbial peptides.
The efficacy of immunotherapies, such as immune checkpoint inhibitors, which are designed to boost the patient’s own immune system, has been shown to correlate with mutational burden.1 Repertoires of T cells that target neoantigens have been identified in patients and have been shown to coevolve with changes in the spectrum of neoantigens over time. In patients who were successfully treated with adoptive T-cell therapy, the T cells responsive to neoantigens disappeared concomitantly with the loss of cognate antigen, whereas newly occurring mutations were paralleled by new T-cell reactivity.2 These discoveries pave the way for new personalized and truly tumor-specific immunotherapies.
Patient-specific candidate neoantigens may be computationally predicted on the basis of the...