Tweaking protein may improve colorectal cancer outcomes

According to new research from Mayo Clinic, colorectal cancer outcomes may improve by genetically altering an immune-regulatory protein in cancer cells, making the cells more vulnerable to chemotherapy. The findings, published in August 2019 in the journal Oncogene, indicate that increasing the expression of the PD-L1 protein in colorectal cancer cells can improve the effectiveness of chemotherapy.

"These findings, if verified by subsequent research, suggest that the level of tumor cell PD-L1 may be important in drug sensitivity and suggest that enhancing PD-L1 expression may be a potential strategy to improve treatment outcomes in this malignancy," said Frank A. Sinicrope, M.D., a medical oncologist and gastroenterologist at Mayo Clinic in Rochester, Minnesota. Dr. Sinicrope is also co-director of the Gastrointestinal Cancer Program in Mayo Clinic Cancer Center and corresponding author of the published study results.

PD-L1 is an immune checkpoint protein that interacts with another protein, PD-1, to negatively affect cell functions and enable tumor cells to evade the body's immune system. Research has shown that interrupting the PD-L1/PD-1 interaction can enhance attacks on anti-tumor immunity.

However, the Mayo Clinic study describes another function of PD-L1: its effect on proteins that regulate tumor cell death. Deleting the PD-L1 gene suppressed two proteins that are associated with increased chemotherapy-induced cell death. In contrast, restoring PD-L1 expression reversed the suppression of these proteins.

"We sought to determine the relevance of our findings for PD-L1 in patients with colorectal cancer," Dr. Sinicrope said. "To do so, we utilized the Cancer Genome Atlas database of the National Cancer Institute to examine the association of PD-L1 expression with the survival of patients with colon cancer."

The study found that increased tumor cell PD-L1 expression was associated with better survival in patients expected to have received chemotherapy, which is the standard of care for patients with stage III and stage IV cancers, Dr. Sinicrope said. "This suggests a broader role for PD-L1 as a possible predictive biomarker for how patients will respond to cancer treatment, though more research is needed to address this issue," he said.

The study also found that the BRAF oncogene, a gene that can transform a cell into a cancer cell, can regulate the expression of PD-L1. When the BRAF oncogene is mutated, it can increase PD-L1 expression in colorectal cancer cells, according to the study.

"Current therapies targeting PD-L1 are mainly focused on blocking or disrupting its function in tumor cells," said Haidong Dong, M.D., Ph.D., a tumor immunologist at Mayo Clinic in Rochester, Minnesota, and co-author of the published study. "This work suggests that enhancement of PD-L1 expression in tumor cells may promote the efficacy of chemotherapy, at least in colon cancer. It is an idea-changing discovery that, if validated in clinical trials, would bring more benefit to patients with colon cancer that is resistant to current chemotherapy."

Related

• Frank A. Sinicrope, M.D.
• Haidong Dong, M.D., Ph.D.
• Gastrointestinal Cancer Program
• Colorectal cancer
• The Cancer Genome Atlas Program
• BRAFV600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenograft

This article was originally published in Forefront, Mayo Clinic Cancer Center's online magazine, which ceased publication in December 2020.