Dual Gene Deletion Reveals Biomarkers for Predicting Immunotherapy Response

The deletion of two cancer genes, CHD1 and MAP3K7, improves how well tumors respond to cancer immunotherapy and could be used as biomarkers to help predict which patients are most likely to benefit from treatment, new research shows. Researchers at the Wellcome Sanger Institute, Open Targets, Netherlands Cancer Institute and their collaborators used a powerful gene-editing tool called CRISPR in a novel approach that cultured tumor cells together with immune cells from the same individual to measure immune killing of cancer cells. This enabled them to identify which genes make tumor cells more or less vulnerable to immune attack. Published in Cell Reports Medicine, the study sheds light on why some patients are more or less likely to respond to certain types of cancer treatments and could guide the development of more successful personalized treatments. How immunotherapy targets cancer cells Immunotherapy works by harnessing a patient's own immune system to fight cancer. It is used across different stages of cancer, from early to advanced disease, and is often given before surgery to shrink tumors or after to prevent recurrence of the disease. There are different types of immunotherapies. One is called immune checkpoint blockade (ICB), which is used to "release the brakes" on the immune system, allowing immune cells to recognize and attack tumor cells. It is particularly effective for many cancer types such as melanoma and in tumors with faulty DNA repair systems, known as microsatellite instability (MSI). MSI cancers are highly responsive to immunotherapy because their defective DNA repair system creates many mutations, leading to lots of abnormal proteins that are easily detected and attacked by the immune system. However, despite its success in some patients, the response rate of immunotherapy is below 35% in people with solid tumors and scientists don't fully understand why some tumors respond to the immune system while others resist it. Gene editing reveals new insights In a new study, Sanger Institute researchers and their collaborators looked for genes inside cancer cells that influence how well the immune system can attack tumors. The researchers applied a tool called genome-wide CRISPR-Cas9 screening. This allowed them to switch off genes one-by-one across the entire genome to observe how cancer cells responded to immune signals. To measure the killing of cancer cells by immune cells, the researchers developed a new CRISPR method where tumor cells and immune cells from the same individual are cultured together, also known as a co-culture. The researchers discovered that two genes, CHD1 and MAP3K7, are key regulators of immune sensitivity. When either of these genes are knocked out, the cancer cells become more sensitive to the immune system—especially to key immune signals such as interferon-gamma (IFN-γ) and to direct attack by T-cells, which are some of the most important cancer-killing immune cells. When both genes were switched off at the same time, cancer cells became even more vulnerable. This suggests the loss of CHD1 and MAP3K7 changes how cancer cells respond to inflammatory signals, pushing them towards self-destruction when the immune system is activated. Potential for personalized cancer treatment The researchers then tested these findings in mouse models and found that tumors lacking these genes responded far better to immunotherapy as they attracted a higher level of cancer-killing immune cells. Finally, analysis of patient data showed that cancers with low levels of CHD1 or MAP3K7 expression were more likely to respond to immunotherapy. Therefore, the researchers suggest that CHD1 and MAP3K7 could potentially help identify patients who are most likely to benefit from immunotherapy and open up new ways to improve personalized treatment, and outcomes, for people with cancer. "We found that when cancer cells lose two genes, CHD1 and MAP3K7, they become much easier for the immune system to attack, as without these active genes, cancer cells respond very differently to immune signals. This loss exposes a weakness that immune cells can take advantage of," said Alex Watterson, co-first author formerly at the Wellcome Sanger Institute, and now based at the Babraham Institute. "We saw that patients whose tumors have low expression of these genes are more likely to benefit from immunotherapy. In the future, these new biomarkers could guide doctors by predicting who will respond to treatment and enable more personalized cancer care," said Dr. Matthew Coelho, senior author at the Wellcome Sanger Institute and Open Targets. "Immunotherapy can be life-changing for some people with cancer, but for many patients it simply doesn't work, and it's been a mystery why that is the case. Understanding the mechanism behind why some tumors respond and others resist treatment is one of the biggest conundrums that our research is one step closer to helping to solve," said Dr. Mathew Garnett, co-senior author at the Wellcome Sanger Institute and Open Targets.