Experts from Cedars-Sinai Cancer have analyzed patient samples, along with studies conducted in animal models, to identify a novel immune checkpoint pathway to treat hepatocellular carcinoma, the most common form of liver cancer.

Ekaterina Koltsova, Ph.D., is a research scientist II at Cedars-Sinai Medical Center in Los Angeles, CA. Photo courtesy: © 2021 – 2022 Cedars-Sinai Cancer. Used with permission.

This big data analysis, coupled with existing immune-boosting therapies, provides a new frontier for treatment strategies.

The findings of the study—centered on the discovery of a novel role for the Interleukin-27 (IL27) signaling pathway in liver cancer—were published in the peer-reviewed journal Cancer Discovery, a journal of the American Association for Cancer Research. [1]

Immune response
IL27) is a cytokine belonging to the IL6/IL12 cytokine family. IL27 plays a role in innate as well as adaptive immunity. [2][3]

In adaptive immunity, IL27 was shown to synergize with IL12 to promote IFNγ production by CD4, CD8 T cells, and NKT cells. IL27 was also identified as an early initiator of Th1 differentiation.[2]

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In innate immune, IL27 was demonstrated to induce the production of IL1, TNFα, IL18 and IL12 in monocytes, and IL1 and TNFα in mast cells. Recent studies have revealed that IL27 also inhibits differentiation of Th17 cells. [2]

While these previous studies suggest the IL-27 pathway may play an important role in the immune response of various inflammatory diseases, in the current study the scientists have, for the first time, identified this new mechanism in liver cancer.

“We found that disrupting the IL-27 pathway in mice prevented liver tumors from growing,” said Ekaterina Koltsova, MD, Ph.D., the corresponding and senior author of the study, a faculty member of Cedars-Sinai Cancer and the departments of Medicine and Biomedical Sciences.

“This exciting discovery supports the idea of therapeutic antibodies or other molecules to block the IL-27 pathway, and in turn, activate an anti-cancer immune response in liver cancer.”

The aim, Koltsova says, is that activating the immune response will enable a liver cancer patient’s immune system to kill the cancerous cells.

“This research also led us to the understanding that we can inhibit the IL-27 pathway alone, or together with other well-known immunotherapies, to tackle otherwise hard-to-treat cancers, like liver cancer,” Koltsova explained.

Sergei Grivennikov, Ph.D., is a Professor of Medicine and a Professor of Biomedical Sciences. Photo courtesy: © 2021 – 2022 Cedars-Sinai Cancer. Used with permission.

Liver cancer
Liver cancer is considered a major contributor to the worldwide cancer burden. In recent decades, the incidence rates have in many countries increased.

As the principal histologic type of liver cancer, hepatocellular carcinoma (HCC) accounts for the great majority of liver cancer diagnoses and deaths.

Hepatitis B virus (HBV) and hepatitis C (HCV) remain, at present, the most important global risk factors for HCC, but, as a result of HBV vaccination of newborns, their importance will likely decline in the coming years.

And while these preventive approaches will potentially curb a proportion of new cases, researchers suggest liver disease and cancer are rising because of the increased prevalence of fatty liver disease, coupled with the epidemic of obesity and Type 2 diabetes (T2DM) — as well as individuals’ increased exposure to environmental toxins and pollutants.

Respond to immunotherapies
Today, patients diagnosed with liver cancer, including hepatocellular carcinoma, do not frequently respond to immunotherapies, and survival rates remain low.

“We know that many patients with chronic liver disease and inflammation are at high risk for developing hepatocellular carcinoma, which makes finding effective treatment increasingly important,” said Sergei Grivennikov, Ph.D., professor of Medicine and Biomedical Sciences and a co-senior author of this study.

“This pivotal basic research may pave the road for new treatment options for this devastating disease.”

In the study, researchers focused both on laboratory research conducted in mouse models testing the IL-27 pathway and on samples collected from patients with liver cancer. Specifically:

  • In the laboratory, scientists manipulated the expression of the IL-27 receptor, then studied its effect on disease development and identified liver immune cells called natural killer (NK) and innate lymphoid cells as the most affected by IL-27.
  • Once cancer developed, researchers tested experimental immunotherapies that block IL-27 and showed that this inhibited liver cancer growth.
  • Using publicly available big data sources to perform original analyses, the research team looked for connections between the IL-27 pathway—and other molecules—and liver cancer progression in patients.

“Taken together, our data suggest that blocking the IL-27 pathway and combining the right immunotherapy may provide a new therapeutic strategy in liver cancer,” said Koltsova. “This advance may also provide new opportunities for preventive approaches in high-risk patients with nonalcoholic liver disease and liver fibrosis who likely will develop hepatocellular carcinoma.”

Dan Theodorescu, MD, Ph.D., is PHASE ONE Foundation, Distinguished Chair, Director, Cedars-Sinai Cancer, Professor, Surgery and Professor, Pathology and Laboratory Medicine. Photo courtesy: © 2021 – 2022 Cedars-Sinai Cancer. Used with permission.

As a next step, Cedars-Sinai Cancer researchers—including Aleksandra Mazitova, a research associate in the Koltsova Laboratory and a co-first author of the study—aim to further elucidate how the IL-27 pathway regulates other cells in the liver. From there, they can determine the optimal strategies to best target this pathway to produce effective immune responses in other cancers or other diseases dependent on IL-27 for control of immune function and inflammation.

“This exceptional work in liver cancer is particularly exciting because it addresses a major human cancer where less progress has been made compared to other tumors,” said Dan Theodorescu, MD, Ph.D., director of Cedars-Sinai Cancer.

“This study is also a prime example of how our cancer center works to address disparities in communities with a high prevalence of risk factors for liver cancer, especially the Latin/x community.”

* Ekaterina Koltsova received research funding from Surface Oncology Inc. to investigate IL-27 blockade in mouse models of hepatocellular carcinoma. She is also an inventor on pending patent applications associated with the topic presented in this article.

[1] Aghayev T, Mazitova AM, Fang JR, Peshkova IO, Rausch M, Hung M, White KF, Masia R, Titerina EK, Fatkhullina AR, Cousineau I, Turcotte S, Zhigarev D, Marchenko A, Khoziainova S, Makhov P, Tan YF, Kossenkov AV, Wiest DL, Stagg J, Wang XW, Campbell KS, Dzutsev AK, Trinchieri G, Hill JA, Grivennikov SI, Koltsova EK. Interleukin-27 signaling serves as an immunological checkpoint for innate cytotoxic cells to promote hepatocellular carcinoma. Cancer Discov. 2022 Jun 20:candisc.1628.2020-11-7 00:59:46.747. doi: 10.1158/2159-8290.CD-20-1628. Epub ahead of print. PMID: 35723626.
[2] Carl JW, Bai XF. IL27: its roles in the induction and inhibition of inflammation. Int J Clin Exp Pathol. 2008 Jan 1;1(2):117-23. PMID: 18784808; PMCID: PMC2480558.
[3] Kastelein RA, Hunter CA, Cua DJ. Discovery and biology of IL-23 and IL-27: related but functionally distinct regulators of inflammation. Annu Rev Immunol. 2007;25:221-42. doi: 10.1146/annurev.immunol.22.012703.104758. PMID: 17291186.

Featured image: Handling histological liver tissue sample

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