Handling histological liver tissue sample
Handling histological liver tissue sample

A study at The University of Texas MD Anderson Cancer Center, funded, in part, by the National Institutes of Health (NIH)* discovered a cellular pathway tied to cancer that may be beneficial in reducing side effects and extending duration of immunotherapy in some patients with hepatocellular carcinoma (HCC), a tumor of the parenchymal cells of the liver.[1]

Primary liver cancer is the sixth most commonly occurring cancer in the world and the second largest contributor to cancer mortality and with approximately 80%, hepatocellular carcinoma represents the most common histology.[2]

Li-Chuan Chan, Ph.D., a postdoctoral fellow in the Department of Molecular and Cellular Oncology at The University of Texas MD Anderson Cancer Center.

The prevalence of HCC varies around the globe and strongly depends of a select number of risk factors, including chronic infection with hepatitis B and hepatitis C, alcohol consumption, tobacco smoking, obesity, and diabetes.

Overall, 44% of cases of HCC can be attributable to chronic hepatitis B infection, with the majority of cases occurring in Asia and Hepatitis C (21% of cases of HCC), while lifestyle risk factors such as alcohol consumption and obesity generally account for a larger percentage of cases in North America and Europe. [3]

Treatment options
HCC has long been a complex and difficult disease to treat. While the U.S. Food and Drug Administration (FDA) has approved the multikinase inhibitors sorafenib (Nexavar®; Bayer) in first line treatment and regorafenib Stivarga®; Bayer) in second-line treatment of HCC, these agents have been shown to extend overall survival by fewer than 3 months with. on avaerage, low overall response rates.

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In contrast, another agent, nivolumab (Opdivo®; Bristol-Myers Squibb Company) has been approved for advanced HCC refractory to sorafenib, demonstrated a 20% objective response rate in advanced HCC.

Research has shown that HCC occurs, in many cases, the context of chronic inflammation related to viral infections, heavy alcohol consumption, obesity, or nonalcoholic fatty liver disease. And high levels of an inflammatory cytokine, a protein known as interleukin-6 (IL-6), in tumor region or plasma are generally correlated with poor prognosis in advanced HCC. [4][5]

Cellular pathway
Researchers looked at a cellular pathway formed when 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. Study results were published online in the July 15, 2019 edition of the Journal of Clinical Investigation.[1]

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 death ligand 1 (PD-L1), an immune checkpoint protein known to suppress the immune system, also known as B7 homolog 1 and CD274).

The engagement of PD-L1 with the programmed cell death protein-1 (PD-1) receptor on T cells activates co-inhibitory signaling to suppress the function of cytotoxic T lymphocytes (CTLs). This allows cancer cells to evade immune surveillance

Boosting T-cell killing effects
“Our results demonstrated that anti-IL-6 antibodies, when combined with anti-Tim-3 antibodies, boosted T-cell killing effects in mouse models,” said Li-Chuan Chan, Ph.D., a postdoctoral fellow in the Department of Molecular and Cellular Oncology

“We identified a mechanism regulating PD-L1 glycosylation initiation, suggesting that a combination of anti-IL-6 and anti-Tim-3 as an effective marker-guided therapeutic strategy,” Chan added.

The researchers looked at the correlation between IL-6 and PD-L1 expression in tumor samples from 183 liver patients and found that patients with high IL-6 expression also had elevated PD-L1 expression.

Previous MD Anderson studies reported that high IL-6 levels are associated with poorer prognosis in liver cancer patients. 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,” Chan explained

“Together, these findings may provide a potential mechanism on how activated JAK1 translocates to other cellular compartments and warrant further investigation in the future,” he noted

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,” Chan concluded.

* In addition to the National Institutes of Health (NIH), other funders of the study included 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.

[1] Chan LC, Li CW, Xia W, Hsu JM, Lee HH, Cha JH, Wang HL, Yang WH, et al. IL-6/JAK1 pathway drives PD-L1 Y112 phosphorylation to promote cancer immune evasion. J Clin Invest. 2019 Jul 15;130. pii: 126022. doi: 10.1172/JCI126022. eCollection 2019 Jul 15. [Pubmed][Article]
[2] Baecker A, Liu X, La Vecchia C, Zhang ZF Worldwide incidence of hepatocellular carcinoma cases attributable to major risk factors.Eur J Cancer Prev. 2018 May;27(3):205-212. doi: 10.1097/CEJ.0000000000000428. [Pubmed]
[3] McGlynn KA, Petrick JL, London WT. Global epidemiology of hepatocellular carcinoma: an emphasis on demographic and regional variability. Clin Liver Dis. 2015 May;19(2):223-38. doi: 10.1016/j.cld.2015.01.001. Epub 2015 Feb 26 [Article]
[4] Llovet JM, Zucman-Rossi J, Pikarsky E, Sangro B, Schwartz M, Sherman M, Gores G. Hepatocellular carcinoma. Nat Rev Dis Primers. 2016 Apr 14;2:16018. doi: 10.1038/nrdp.2016.18.[Pubmed]
[5] Park EJ, Lee JH, Yu GY, He G, Ali SR, Holzer RG, Osterreicher CH, Takahashi H, Karin M. Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell. 2010 Jan 22;140(2):197-208. doi: 10.1016/j.cell.2009.12.052. [Pubmed]

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