Immune checkpoint inhibitors are among some of the most exciting new drug targets that researchers and clinicians have added to their arsenal in the fight against deadly diseases such as cancer. While much is known about how these checkpoint pathways operate, there are still some knowledge gaps that need to be addressed, in order to fully understand the potential of these druggable systems.
Immune checkpoints are typically surface proteins that cancer cells use to evade the immune response. These surface proteins are critical for cancer cell growth and drugs targeting these proteins have revolutionized the management of patients with a wide array of cancers. Finding a mechanism to degrade these immune checkpoints may allow the immune system to kill cancer cells.
Now, a team of investigators from Boston University School of Medicine (BUSM) has discovered the protein casitas B lymphoma (c-Cbl) has the ability to degrade the checkpoint protein PD-1, a protein found on T cells that helps keep them from attacking other cells in the body. Manipulating c-Cbl’s ability to regulate expression of PD-1 may be beneficial in the treatment of certain cancers including melanoma, bladder, kidney, breast, and non-small lung cancers.
Findings from the new study were published recently in Scientific Reports through an article titled “c-Cbl targets PD-1 in immune cells for proteasomal degradation and modulates colorectal tumor growth.”
“c-Cbl is an E3 ubiquitin ligase and a negative regulator of colorectal cancer,” the authors wrote. “Despite its high expression in immune cells, the effect of c-Cbl on the tumor microenvironment remains poorly understood.”
Cancer cells often increase their expression to “trick” the immune system and avoiding being detected as foreign or harmful and thus avoid being attacked or destroyed. Manipulating c-Cbl’s ability to regulate the expression of PD-1 may be incredibly beneficial in the treatment of these cancers.
For the current study, the researchers examined the effect of c-Cbl on immune cells on experimental models lacking one copy of the c-Cbl gene. Tumor cells were implanted in these models and growth of the tumors was compared between models lacking the gene and unmodified models which served as controls. The researchers found that tumor growth was greater in the genetically modified model.
“We demonstrate that c-Cbl alters the tumor microenvironment and suppresses Programmed cell death-1 (PD-1) protein, an immune checkpoint receptor. Using syngeneic CRC xenografts, we observed significantly higher growth of xenografts and infiltrating immune cells in c-Cbl+/− compared to c-Cbl+/+ mice,” the authors explained. “Tumor-associated CD8+ T-lymphocytes and macrophages of c-Cbl+/− mice showed 2–3-fold higher levels of PD-1. Functionally, macrophages from c-Cbl+/− mice showed a 4–5-fold reduction in tumor phagocytosis, which was restored with an anti-PD-1 neutralizing antibody suggesting regulation of PD-1 by c-Cbl. Further mechanistic probing revealed that C-terminus of c-Cbl interacted with the cytoplasmic tail of PD-1. c-Cbl destabilized PD-1 through ubiquitination- proteasomal degradation depending on c-Cbl’s RING finger function.”
The BUSM investigators were encouraged by their findings and noted that it may be possible in the near future to develop therapies that will inhibit tumor growth by activating c-Cbl protein.
“While drugs targeting PD-1 are currently available for clinical use and such agents command a global market cap of more than $3 billion, only a small fraction of cancer patients respond to them,” concluded senior study investigator Vipul Chitalia, MD, PhD, associate professor of medicine at BUSM. “This trend suggests a need for agents that work simultaneously on more than one cancer-causing mechanism. Activating c-Cbl will degrade several proteins that contribute to tumor formation allowing the effects of its actions to go above and beyond PD-1 medications alone.”