Increasing PD-L1 Expression in Colorectal Cancer Cells May Improve Effectiveness of Chemotherapy

A study conducted by researchers at Mayo Clinic in Rochester and Mayo Clinic in Florida, supported in part by a grant from the National Cancer Institute, demonstrates that 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 Oncogene, indicate that increasing the expression of the programmed death ligand 1 (PD-L1) protein, an immune checkpoint protein, in colorectal cancer cells can improve the effectiveness of chemotherapy. [1]

“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,” noted Frank Sinicrope, MD, a Mayo Clinic medical oncologist and gastroenterologist.

Sinicrope is co-director of the Gastrointestinal Cancer Program at Mayo Clinic and corresponding author of the study.

Immune checkpoint protein
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, in their study report, researchers at Mayo Clinic 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,” Sinicrope says.

“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,” he added.

Better survival
The study found that increased tumor cell PD-L1 expression was associated with better survival among patients expected to have received chemotherapy, which is the standard of care for patients with stage 3 and stage 4 cancers, according to Sinicrope.

“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 says.

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,” explained Haidong Dong, MD, Ph.D., a Mayo Clinic tumor immunologist and co-author of the 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,” Dong concluded.

Reference
Feng D, Qin B, Pal 2, Sun L, Dutta S, Dong H, Liu X, et al. BRAFV600E-induced, tumor intrinsic PD-L1 can regulate chemotherapy-induced apoptosis in human colon cancer cells and in tumor xenografts. Oncogene. 2019 Aug 12. doi: 10.1038/s41388-019-0919-y. [Pubmed][Article]