Role of IL-6/JAK1 Pathway in the Treatment of Hepatocellular Carcinoma
A recent study published by Chan et al in the Journal of Clinical Investigation found a cellular pathway associated with cancer may be beneficial in reducing side effects and extending duration of immunotherapy in some patients with hepatocellular carcinoma.
IL-6/JAK1 Pathway
Researchers looked at a cellular pathway formed when a protein known as interleukin-6 (IL-6) activates an enzyme called Janus kinase 1 (JAK1), and the potential for anti–IL-6 antibodies and anti–T-cell immunoglobulin mucin-3 (anti–Tim-3) in augmenting immunotherapy.
The IL-6/JAK1 pathway is often observed in tumors and may play a role in cancer evasion by regulating a crucial cellular function in programmed cell death ligand 1 (PD-L1).
Findings
“Our results demonstrated that anti–IL-6 antibodies, when combined with anti–Tim-3 antibodies, boosted T-cell killing effects in mouse models,” said first study author Li-Chuan Chan, PhD, a postdoctoral fellow in the Department of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center. “We identified a mechanism regulating PD-L1 glycosylation initiation, suggesting that a combination of anti–IL-6 and anti–Tim-3 is an effective marker-guided therapeutic strategy.”
The researchers looked at the correlation between IL-6 and PD-L1 expression in tumor samples from 183 patients with hepatocellular carcinoma and found that patients with high IL-6 expression also had elevated PD-L1 expression. Previous studies found that high IL-6 levels are associated with poorer prognosis in patients with liver cancer. The team’s new findings suggested that IL-6 is “physiologically significant and clinically relevant” to PD-L1 expression in liver cancer.
“We also found that the IL-6/JAK1 pathway contributed to PD-L1 phosphorylation, which appeared to be the dominant driver of cancer immune evasion in a liver cancer mouse model,” said Dr. Chan. “Together, these findings may provide a potential mechanism on how activated JAK1 translocates to other cellular compartments and warrant further investigation in the future.”
The study also pointed to a potential benefit for lessening immunotherapy side effects, which sometimes can shorten the amount of time patients can stay on treatment. Immune checkpoint inhibitors have been shown to stimulate the production of IL-6 serum, which can cause arthritis, Crohn’s disease, and a psoriasiform dermatitis.
“Therefore, blocking the IL-6 pathway may resolve these side effects and extend the duration of immunotherapy,” concluded Dr. Chan.
Disclosure: The study was funded by the National Institutes of Health, the Cancer Prevention & Research Institute of Texas, The University of Texas MD Anderson Cancer Center-China Medical University and Hospital Sister Institution Fund, the Ministry of Health and Welfare, China Medical University Hospital, the Ministry of Science and Technology Overseas Project for Post Graduate Research, the National Research Foundation of Korea, and the MD Anderson Odyssey Fellowship Program. For full disclosures of the study authors, visit jci.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
