Proteins identified as key players in immunotherapy resistance for colorectal cancer

A discovery by Mayo Clinic researchers may help explain why immunotherapy hasn't been helpful for many patients with metastatic colorectal cancer. In findings published in Clinical Cancer Research, the team identified specific proteins - fibronectin and smooth muscle actin - within colorectal cancer tissues that are associated with resistance to immunotherapy treatment.

Immunotherapy is a major advance in treating cancer, but many patients, including those with metastatic colorectal cancer, do not respond to it. Until now, researchers have not known why.

We need predictive biomarkers to guide the selection of immunotherapy for patients. Identifying those who may have resistance to treatment can be useful, because then we can spare them from receiving treatment that may not be beneficial and could produce significant toxicities."

Frank Sinicrope, M.D., medical oncologist, gastroenterologist, senior author of the study

The research team used digital spatial profiling, an advanced technology that simultaneously analyzes the expression of multiple proteins and where they are located within tissues. This approach allowed researchers to zoom in to get a bird's eye view of a tumor that includes proteins both within and surrounding the tumor cells and how they interact.

Dr. Sinicrope compares the spatial tools to an aerial view of a neighborhood where one can see relationships between driveways, houses, yards and neighboring structures. Similarly, this detailed view provides physicians and researchers with critical information about the proteins in and around a patient's cancer, potentially informing the best treatment for the patient. 

"We wanted to learn more about the patients who did not respond to immunotherapy. We investigated the leading edge of the tumor where cancer cells are invading and where the immune system is attempting to fight the cancer," says Dr. Sinicrope. "It's like a battle going on here and we're getting a snapshot into who is in attendance."

The researchers focused on 10 regions at the invasive margin of a tumor. They applied digital spatial profiling to investigate 71 distinct proteins in both the tumor's epithelial compartment and the surrounding stromal compartment. Fibronectin and smooth muscle actin are two extracellular matrix proteins that were found in the epithelial region of the tumor and were associated with resistance to immunotherapy and shorter time before disease progression.

Upon further analysis, the researchers observed that cancer-associated fibroblasts were producing these proteins. The evidence, they say, suggests that these proteins can contribute to suppression of the anti-tumor immune response.

The discovery offers a step toward more personalized and effective colorectal cancer treatments.