▎ WuXi AppTec content team editor
Recently, Academician Fan Jia of Zhongshan Hospital Affiliated to Fudan University, Zhu Di, Researcher of Fudan University, and Associate Professor Xu Yang of Zhongshan Hospital Affiliated to Fudan University have collaborated to publish a paper online in cancer authoritative journal Cancer Discovery, proposing a new strategy for combined drug use for the treatment of hepatocellular carcinoma (HCC), which is expected to solve the problem of immunotherapy resistance.
The study found that interferon α activate immune responses by remodeling the tumor immune microenvironment through glucose metabolism, and in combination with immune checkpoint inhibitors (ICBs), it can enhance antitumor activity in patients with liver cancer. "This is a new idea for old drugs and new uses, so that immunotherapy can be added to the tiger." Researcher Zhu Di said.
▲ Old drugs are new and new, such as tiger wings (image source: provided by the study authors)
Interferon α is a class of endogenous regulators secreted by immune cells, so interferon α recombinant protein drugs have a natural safety, and are widely used in virus prevention and control, immunomodulation and other fields. However, interferon α itself has a wide range of effects and models, and the efficacy of monotherapy anti-tumor is not good. How to rationally use interferon α in specific tumor immunotherapy has become a major scientific problem with great clinical research value.
The hepatic surgery team of Zhongshan Hospital Affiliated to Fudan University has deeply cultivated the clinical application of interferon anti-liver cancer. Previous work has been found that specific patients receiving interferon therapy can significantly improve postoperative survival. In 2022, the guidelines for the diagnosis and treatment of primary liver cancer led by Academician Fan Jia included interferon α as an adjunctive therapy for hepatocellular carcinoma in the evidence level 1.
Image credit: 123RF
In this latest study, Academician Fan Jia's team found based on clinical cohort studies that for unresectable liver cancer, the combination of interferon α and anti-PD-1 antibodies can significantly reduce the tumor volume and have a significant effect on inhibiting liver cancer lung metastasis.
In the animal model, the research team further explored the molecular mechanisms behind it. Interferon α, anti-PD-1 antibodies, or a combination of two drugs were given to mice with in situ transplant tumor models and spontaneous liver cancer models, and the results showed that the combination treatment group could greatly help immunocompetent mice inhibit liver cancer progression. However, once the cytotoxic T cells (CD8+ T cells) in mice are removed, the therapeutic effect disappears completely.
After using high-throughput flow cytometry to analyze infiltration of immune cells in the tumor microenvironment of different treatment groups in detail, the researchers focused on CD27+ CD8+ T cells. This particular subset of T cells has a strong immune effector function and infiltration is significantly increased in tumors in the combination therapy group.
A series of experiments have shown that interferon-enhanced CD27+CD8+ T cell infiltration in the tumor microenvironment plays a role in correcting the imbalance of glucose metabolism competition between the "tumor-immune microenvironment". Liver cancer cells that can tolerate anti-PD-1 monoclonal antibody exhibit strong glycolysis ability, while interferon can selectively act on specific receptors on the surface of liver cancer cell membranes to inhibit FosB transcription, thereby weakening THE GLYCOLYTIC EFFECT MEDIATED BY HIF1α signaling, reducing the uptake and metabolism of glucose in the microenvironment by hepatocellular carcinoma cells, and significantly increasing the glucose concentration in the tumor microenvironment. Secondly, the high glucose microenvironment can activate the transcription and expression of the co-stimulating molecule CD27 in CD8+ T cells through the mTOR-FOXM1 pathway, thereby significantly enhancing the immunohistocent effect of CD8+ T cells.
To the surprise of the researchers, CD27+CD8+ T cells have excellent killing and proliferative potential, but also highly express the classic "brake molecule" of PD-1, so that they cannot be fully amplified when using interferon monodrugs. This also explains why interferons and immune checkpoint inhibitors can form a perfect linkage, showing excellent combination efficacy in both animal models and clinical patients.
The research team pointed out: "Our research results will greatly expand the adaptation group of immune checkpoint inhibitors, bring new treatment hope to the liver cancer patient population that cannot be operated on and lack drug treatment, and is an important clinical practice for the new use of old drugs." ”
Academician Fan Jia of Zhongshan Hospital Affiliated to Fudan University, Zhu Di, Researcher of Fudan University, and Associate Professor Xu Yang of Zhongshan Hospital Affiliated to Fudan University are the co-corresponding authors of this article. Attending physician Hu Bo, Dr. Yu Mincheng, Technician Ma Xiaolu, Dr. Sun Jialei, and Dr. Liu Chenglong, School of Pharmacy, Fudan University, are the co-first authors of the article. This work was strongly supported by Professor Zhu Xiuxuan of Shanghai Jiahui International Hospital, Professor Zhang Qing of The University of Texas Southwestern Medical Center, Huang Xun, Researcher of Lingang National Laboratory, and Engineer Nie Yanyan of Shanghai Laboratory Animal Center.
Resources:
[1] Bo Hu et al., (2022) Interferon-a potentiates anti-PD-1 efficacy by remodeling glucose metabolism in the hepatocellular carcinoma microenvironment. Cancer Discov candisc.1022.2021.
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