The DNA in our cells can accumulate damage over may years. Environmental influences like UV light or cigarette smoke may exacerbate the problem, but since cells have to replicate the genome every time they divide (and some cells divide many times thoughout a lifetime), it's been thought that genetic mutations naturally happen as we age. When those mutations occur in genes that suppress the growth of tumors, or keep cell division under control, cancer can happen. But now, researchers have found that many cancer-linked genes are actively involved in suppressing the immune response to cancer. Genes that have previously been associated with cancer may be playing a different role in influencing the development of disease than we knew.
Reporting in Science, researchers found 100 mutations that can stop the immune system from identifying and responding to cancer. “The shock was that these genes are all about getting around the immune system, as opposed to simply saying 'grow, grow, grow,'" said study leader and geneticist Stephen Elledge, a Howard Hughes Medical Institute Investigator (HHMI) at Brigham and Women’s Hospital.
Researchers know that cancer can evade the immune system, which is why immunotherapies and checkpoint inhibitors were developed. The immune system has to be carefully regulated so it won't respond uncontrollably to infection or cancerous cells and cause massive inflammation. So the body uses immune checkpoints. Inhibitors remove those immune brakes. Immunotherapy that uses gene editing can also prime the immune defenses to fight cancer. But these treatments don't always work, and some have serious side effects.
In this study, CRISPR tools were used to edit 7,500 genes, and examine the effect when tumor cells carrying these mutated genes were put in a mouse model. One type of mice had a functional immune system, while another group did not. When tumors grew in the mice, the researchers used genetic sequencing to identify the genes in the tumors that were most mutated, which revealed how the tumor cells had continued to evolved once they were in the live model. This revealed that defective tumor suppressor genes often appeared in the tumors; there was a selective pressure on the tumor cell genomes that would enable those with mutated tumor supressor genes to continue to grow.
One gene in particular, GNA13 was found to shield cancer cells from the T cells of the immune system, when GNA13 carried mutations.
Elledge suggested that there is an ongoing evolutionary battle between cancer and the immune system, with tumor cells armed with hundreds of potential strategies to stop the body’s attack. But, this work could reveal new ways to attack cancer.