Data in a study by Mayo Clinic Cancer Center researchers indicates that the level of tumor cell PD-L1, a protein that acts as a brake to keep the body’s immune responses under control, may be an important factor for sensitivity to chemotherapy in colorectal cancer treatment. The study was published Friday, July 2, in Oncogene.
“We have identified a mechanism by which absent or low levels of tumor cell PD-L1, which is commonly found in solid tumors, can confer resistance to chemotherapy in colorectal cancer,” says Frank Sinicrope, M.D., a Mayo Clinic medical oncologist and gastroenterologist, and the study’s author.
PD-L1 is a protein that is increased on some human cancer cells and is a target for immunotherapy, but its role in response to chemotherapy is poorly understood.
“Our study found that the loss of PD-L1 in tumor cells was shown to enhance JNK signaling that modifies a protein called BIM, resulting in its inactivation such that it cannot mediate the killing of cancer cells,” says Dr. Sinicrope. He says targeting JNK may be a promising strategy to overcome drug resistance in cancer cells with low or absent tumor cell PD-L1 expression, which is typical in most colorectal cancers.
“Our results identify an important mechanism by which low or absent levels of PD-L1 protien may contribute to lack of response to chemotherapy,” says Dr. Sinicrope. He says the findings suggests a potential new strategy to target the JNK pathway, thereby sensitizing colon cancer cells to chemotherapy.
“We have identified an important role of PD-L1 in colon cancer cells that is independent of it serving as a target for cancer immunotherapy,” says Dr. Sinicrope. “Our findings demonstrate that frequently identified low or absent PD-L1 levels in human colorectal cancer cells can be a cause of resistance to chemotherapy.” He says the study findings indicate that the mechanism of this effect is mediated by enhanced JNK signaling, and inhibiting this signaling may be a promising strategy to overcome resistance to drug therapy in colorectal cancer treatment.
Reference: Sun, L., Patai, Á.V., Hogenson, T.L. et al. Irreversible JNK blockade overcomes PD-L1-mediated resistance to chemotherapy in colorectal cancer. Oncogene (2021). https://doi.org/10.1038/s41388-021-01910-6
Provided by Mayo Clinic