Tumors are heterogenous masses of cells that rapidly divide. Many cells have different mutations, functions, and ways to avoid immune cell detection and drive tumor progression. The heterogeneity of tumors is a major obstacle to complete cancer eradication. Many treatments cannot eliminate the entire cancer because not all tumor cells are the same. As a result, the treatment that is designed to target a specific mutation or aspect of cell function is not applicable to every tumor cell type. Researchers have worked to detect various biomarkers that help target most cancer cells. Unfortunately, the lack of definitive surface proteins restricts cancer therapy.
Cancer cells find ways to avoid cell death even after an identifiable surface marker is discovered. In some cases, the tumor cell will lose that marker to adapt to the immune response. The marker may become inverted into the cell, or it will fall off the surface. Additionally, the expression of other biomarkers can predict the efficacy of certain therapies. For example, the increased expression of PD-L1 on tumor cells prevents T cells from recognizing the cancer. The corresponding therapy, anti-PD-L1, blocks this surface protein and restores T cell antitumor function. Consequently, PD-L1 expression is a predictive marker that can inform anti-PD-L1 efficacy. Scientists are currently investigating other biomarkers to better predict treatment outcome and improve personalized medicine based on marker expression.
A recent paper in Oncotarget, by Dr. Crismita Dmello and others, demonstrate that CHEK2 might serve as an effective biomarker that can be targeted to improve immunotherapy in solid tumors. Dmello is an Assistant Professor of Neurological Surgery at the Northwestern University Feinberg School of Medicine. Her work focuses on therapeutic targeting of cancer. Previously, her work has investigated the role of cancer metastasis and how cancer changes its shape to more easily travel throughout the body.
CHEK2 is a gene associated with DNA repair; however, scientists are suggesting that it could help predict therapeutic response. Researchers stated that the lack of CHEK2 expression sensitizes tumor cells to immunotherapy. Specifically, CHEK2 helps enable precise DNA repair. When this protein is downregulated, cells turn toward more error-prone methods to fix DNA. Consequently, these cells are more susceptible to mutational burden. Interestingly, analyses indicate that tumors with less CHEK2 expression have more mutations that the immune cells can recognize compared to cancers that have an increase in CHEK2 expression. Additionally, a pathway known as ‘cGAS-STING’ detects DNA damage. With the inability for a cell to repair DNA (due to lack of CHEK2), the cGAS-STING pathway will trigger an immune response. As a result, the high mutational burden generates tumor proteins or ‘neoantigens’ that are recognizable to the endogenous immune system. This alters the environment around the tumor toward a robust antitumor immune response.
Dmello and others explain the correlation between CHEK2 and tumor progression. Scientists can now begin using this information to better predict therapies and improve personalized medicine. Currently, clinical trials are using a standard form of immunotherapy with a CHEK2-inhibitor. While the trials are just starting, scientists hope to improve standard-of-care therapy in patients with aggressive or refractory solid tumors.
Paper, Oncotarget, Crismita Dmello, Northwestern University Feinberg School of Medicine