Mutations are alterations of an organism’s genomic nucleic acid sequence. There are numerous reasons for mutations. They can, for example, be caused by chemical agents or radiation but can also occur spontaneously, for example, due to error-prone cell replication processes. Especially when multiple genes for cell growth, differentiation, cell division, or survival are altered by mutations, a normal cell can transform into a cancer cell. The number of mutations in a cancer cell can be specified as tumor mutational burden (TMB). This number is given as mutations per megabase (Mut/Mb).
Somatic mutations are only present in tumor tissue but not in normal, healthy tissue. The TMB is a promising predictive biomarker that measures a tumor’s number of somatic mutations. Some cancer types, such as Ewing sarcomas or acute myeloid leukemia (AML), have low mutation rates. In contrast, other cancer types, such as melanomas or lung squamous cell carcinomas, have high mutation rates. Thus, tumors can be classified into low, intermediate, or highly mutated, resulting in low, intermediate, or high TMB values. Knowing a tumor’s TMB might help in planning the best treatment strategy. In a promising cancer treatment, only the cancer cells are targeted and hurt, while the normal, healthy cells remain unaffected. Immune checkpoint inhibitor therapy is a promising approach that specifically targets altered cancer cells. To understand its functioning, we need to understand how the immune system can be activated.
Both tumor and normal, healthy cells present parts of their protein content on their cells’ surfaces. These protein parts are also called peptides. A tumor cell with many mutations has a higher number of altered proteins, so-called neoantigens. These neoantigens differ from their healthy counterparts. When these tumor neoantigens are now presented on the cancer cell’s surface, they are recognized as foreign since they vary too much from the known proteins from healthy cells. Consequently, the recognition of foreign peptides activates the immune system. The more mutations occur in a tumor, the more neoantigens are presented on the cell’s surface. With increasing numbers of neoantigens presented on the surface, the immune system is activated more easily (see figure 1).
Figure 1 | TMB as a predictive immunotherapeutic biomarker. Cancer cells with a low TMB possess only a few somatic mutations (colored bases). The mutations can lead to altered proteins that are presented on the cell surface as neoantigens, which can be recognized by immune cells. TMB-high cancer cells possess multiple mutations, resulting in a higher number of neoantigens. More neoantigens increase the chance that at least one will activate the immune system.
As high mutation rates correlate with a high TMB, the TMB is a promising predictive biomarker for immunotherapy. In contrast, a low TMB can indicate that the immune cells might not identify the cancer cells. Immune checkpoints are proteins that prevent excessive immune responses. However, some tumor cells also use these immune checkpoints to evade being killed by T-cells. When these immune checkpoints are inhibited, the immune system can target and kill the recognized tumor cells better.
Thus, determining the TMB with whole exome sequencing (WES) can help to identify patients with a high TMB who will probably benefit from immunotherapy.