Researchers have discovered the common oncogene KRAS as a probable reason why several patients with metastatic colorectal cancer (CRC) aren’t responding to immune checkpoint blockade (ICB) therapy.
A study published on March 21, shows how KRAS, a significant mutation in colorectal cancer, endorses metastasis by regulating the immune-suppressive abilities of the tumor microenvironment. The study outcomes show how KRAS and its target genes communicate, backing up further study of an innovative method to enhance ICB treatment.
A chief cause of cancer deaths worldwide is CRC. About 20% of patients have a metastatic illness(at the time of diagnosis), and, in spite of enhancements in treatments, almost 12% of patients live up to five years. The pursuit of novel and effective treatments or developments to existing therapies is vital.
“The majority of colorectal cancer patients do not respond to immune checkpoint blockade therapy, motivating the need for study of mechanisms and combination regimens with targeted therapies and ICB,” Ronald A. DePinho (M.D., professor of Cancer Biology) said. “Our study established an essential role for KRAS in modulating immune microenvironment and primary ICB resistance in advanced CRC.”
DePinho and his team showed how a KRAS-controlled gene named interferon regulatory factor 2 (IRF2) pushes immune suppression and immune therapy repellence in CRCby utilizing a genetically engineered mouse model. They demonstrated how KRAS diminished IRF2 expression, consequently resulting in high expression of a protein-encoding gene, the C-X-C motif chemokine ligand 3 (CXCL3). It binds to its receptor(CXCR2) on the myeloid-derived suppressor cells (MDSC) which indorse immune suppression, metastasis. The academics discovered that restoration of IRF2 expression amplified the CRC sensitivity to ICB therapy.
“This KRAS-IRF2-CXCL2-CXCR3 axis provides a framework for determining which patients may respond better to ICB and potentially identifying combination therapy to enhance ICB therapy effectiveness,” DePinho states. “It remains possible that KRAS mutation status in metastatic CRC could be a predictor of ICB resistance when mediated by IRF2 suppression. Our studies suggest the use of combination CXCR2 inhibitor with ICB therapy in patients with advanced CRC who do not respond to today’s standard of care immunotherapy.”