Fighting liver cancer with cells of the innate immune system

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Investigating the role of the innate immune system in fighting liver cancer: Dr.
Investigating the role of the innate immune system in fighting liver cancer: Dr. Bernd Heinrich. Copyright: Karin Kaiser / MHH
MHH gastroenterologist Dr. Bernd Heinrich is seeking new therapies against hepatocellular carcinoma (HCC), a malignant liver tumor.

MHH gastroenterologist Dr. Bernd Heinrich is seeking new therapies against hepatocellular carcinoma (HCC), a malignant liver tumor. The German Cancer Aid has awarded him the Max Eder Young Investigator Program for this work and is supporting his research with 800,000 euros.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although viral hepatitis and heavy alcohol consumption are important risk factors, non-alcoholic fatty liver (NAFLD) is now one of the main causes of this form of liver cancer due to an unhealthy diet, especially in industrialized countries. Treatment is difficult. There are indications that certain immunotherapies, which are already part of the standard treatment for HCC, have only limited effect in sufferers with NAFLD. Dr. Bernd Heinrich, assistant physician at the Department of Gastroenterology, Hepatology, Infectiology and Endocrinology at Hannover Medical School (MHH), therefore wants to take a different approach. He is focusing on cells of the innate immune system to combat liver cancer. As part of the renowned Max Eder junior research group program of the German Cancer Aid, the physician will receive a grant of 800,000 euros over four years and will be able to establish his own research group. "This gives me a great opportunity to implement my research ideas," says the gastroenterologist. And MHH President Michael Manns is pleased that German Cancer Aid is again awarding the Max Eder Fellowship to a research talent at the university after 2021: "This is a great success for the promotion of young scientists and cancer research at MHH."

Cancer cells paralyze immune cells

Our immune system has two lines of defense. The nonspecific immune defense, known as the innate immune system, is the first defense against most infections and is directed nonspecifically against all pathogens. The second, adaptive immune defense is also called the acquired immune system. Here, the immune system learns to specifically recognize pathogens and form antibodies against the invaders. Standard immunotherapies against tumors target the acquired immune system, which is weakened by the cancer. This is because although some tumors are teeming with immune cells, they do not attack it. The reason: the cancer cells send out signals that paralyze the attack. To wake up the "sleeping" immune cells, checkpoint inhibitors are used: These special antibodies bind to the surface of the immune cells, reactivating them to attack the tumor. "Unfortunately, response rates are low, especially in those with fatty liver," says Dr. Heinrich. He therefore relies on representatives of the first line of defense, the innate lymphoid cells (ILC), to defend against cancer.

Shortly after receiving his doctorate as a postdoctoral fellow at the National Cancer Institute in Bethesda, USA, the gastroenterologist began researching the immune system in cell cultures and animal models of liver cancer and liver metastases. He was particularly interested in the influence of fatty liver disease on the immune response in liver tumors and the role of ILCs in the immediate tumor environment. "The therapeutic potential of ILCs for immunotherapy is still largely unknown," he notes. With his new research group, he first wants to clarify the role these immune cells play in cancer defense and how they communicate with cells of the acquired immune system in the HCC tumor. To do this, samples of human tumor tissue are compared with healthy liver tissue and analyzed to determine which immune cells are active where and when. "In this way, we learn how the network of innate and acquired immune cells functions in the HCC tumor and can better understand the disease," explains Dr. Heinrich.

Cytokines should activate immune cells

In a next step, he wants to change the cells of the innate immune system so that they act more effectively against the cancer cells. This is to be done with the help of cytokines. These messenger substances are produced when the immune system reacts and activate certain defense cells such as ILCs. "In order to avoid the excessive immune reaction also known as cytokine storm, we do not want to give the messenger substances directly to the liver, but only their blueprint in the form of mRNA," explains the junior research group leader. In this way, the activating cytokines are only formed gradually and the cytokine level increases in a controlled manner. The scientist expects a second therapeutic approach from a specific subgroup of ILCs that work like natural killer cells (NK) and initiate programmed cell death in cells that cannot "identify" themselves as healthy body cells - such as tumor cells. This type of ILC appears to be less common in NAFLD patients and could be one reason why this group of HCC patients responds less well to the immunotherapies used to date. The research group now wants to specifically investigate a substance that mobilizes NK-like ILC and could thus improve the anti-tumor response. If the therapeutic approaches work in the mouse model, they could then be tested in a human clinical trial. "This is an ambitious four-year program," Dr. Heinrich admits. "However, we hope to be able to achieve our goals in the four years of funding."