Using computational modelling and experimental approaches, researchers at the Ludwig Center at Memorial Sloan Kettering (MSK), Weill Cornell Medical College in New York and the Icahn School of Medicine at Mount Sinai have reported the interplay between frequently mutated genes in cancer and the immune system. These findings were recently reported in the journal Nature.
The researchers hypothesised that the ‘mutational hotspots’ in cancer drivers such as TP53 reflect a risk and benefits situation for an emerging cancer cell. On the one hand, the mutations in essential hotspot genes provide proliferation and survival benefits to the cancer cells. The protein products of such mutations can invoke the immune system against the tumour. Therefore, if the mutations are pro-tumour in nature, the mutations can be exploited for developing targeted immunotherapies. In contrast, if these mutations have developed as an escape route against immune system surveillance, they will not serve as ideal targets.
The researchers used modelling approaches to predict the emergence of mutational hotspots in a well-known tumour suppressor, TP53 and how its mutated protein influences the fitness of cancer cells and its effect on the immune system. The researchers found that the mutation in TP53 provides a growth advantage to cancer cells, but these cells cannot escape the immune system. The model predicted that specific TP53 hotspot mutations in the bladder and ovarian cancers are more visible to immune system surveillance and hence can be used to design focused immunotherapies. Moreover, such neo-antigens are often displayed in pre-cancerous tissue; they could work as immunotargets as a strategy for the emergence of malignancy.
“Our findings suggest that certain types of mutations most frequently present in tumours are more easily detected by the immune system, and these might prove to be optimal targets for tailored immunotherapies to treat and prevent cancer,” said Ludwig MSK investigator Taha Merghoub. He further added “Our model also accurately anticipated overall survival of patients in several cancer patient cohorts in The Cancer Genome Atlas, including lung cancer patients who had been treated with immunotherapy. Further, it estimates the age of cancer onset for people diagnosed with Li-Fraumeni syndrome, who develop cancer due to inherited mutations in their TP53 genes.”
Hoyos, D., et al. (2022) Fundamental immune–oncogenicity trade-offs define driver mutation fitness. Nature.