In addition to liver cirrhoses, the major risk factors of liver cell carcinoma or hepatocellular carcinoma (HCC) are hepatitis B and C, obesity and metabolic syndrome. HCC is currently experiencing a significant increase in the Western world. Symptoms often do not show up until the later stages of the disease. As HCC frequently remains undiagnosed until the tumour has reached an advanced stage, therapeutic procedures do not usually lead to a complete cure. Since therapeutic treatment is quite difficult, prognosis for long-term survival is also very poor. Only one in five HCC patients is successfully treated. "Eighty percent of all patients diagnosed with HCC have reached a stage that reduces the possibility of successful treatment with available methods; patients with advanced HCC are therefore treated with interventions to extend life and potentially downstage the tumour," says Prof. Dr. Robert Thimme, medical director of the Department of Internal Medicine II at Freiburg University Medical Centre. He considers immunotherapy to be a relatively efficient treatment option for tumours that are difficult to cure. "Although life-prolonging treatments will not eliminate the tumour, they could help to keep the tumour at bay and contribute to prolonging the lives of those affected," Thimme says.

HCC responds very poorly to chemotherapy, which is why HCC therapy has mainly involved surgical and interventional radiological treatments. HCC is traditionally treated with resection, which entails removal of the liver and the implantation of a new one. For patients that are unable to undergo surgical treatment, minimally invasive methods are usually used to eliminate the tumour. Tumour ablation is the local destruction of tumour tissue by way of heat, cold or necrotising substances, where the dead tissue shrinks and forms a scar.

Cancer that is due to liver cirrhosis has to be treated with extra care. "This is because the liver does not function properly and causes problems for patients," says Thimme. "People with HCC due to liver cirrhosis cannot be given such aggressive treatment as one would like." Thimme is specifically focused on the role of the immune system in cancer treatment. Although the mechanisms are still unclear, it is known that people with weakened immune systems have an increased risk for certain types of cancer. The body has the ability to recognise and destroy abnormal cells. Studies have shown that our natural immune response protects the body against the tumour and that the strength of this anti-tumour effect is related to patient survival. The sooner an immune response occurs and the broader it is, the more likely it is that tumour growth will slow down, and thus improve the outcome. "We hope that better tumour response will prolong patient survival time," says Thimme. "If we could improve immune response, we would improve survival time." However, the immune system does not give complete protection against cancer. Even people with intact immune defence systems can develop cancer. Thimme wants to find out why tumours grow in people with intact immune defence systems and why the immune response fails in the long term.

Immune escape and antigen shedding

The body induces a tumour-specific immune response as follows: cancer cells are presented to the immune system, the immune cells attack and accumulate in the tumour. In order for the immune cells to accumulate in and attack the tumour, the immune system's killer cells need to recognise antigens that are expressed by the tumour. But this is often a problem as tumours develop from body cells that carry self-antigens rather than non-self antigens, as pathogens do.

However, attempts made by the immune system to eradicate cancer may inadvertently lead to autoimmunity. To make matters worse, the tumour, even if it carries tumour-specific antigens on its surface, always develops a number of strategies to escape attacks by the immune system (immune escape). Cancers are able to escape attacks by the immune system due to their ability to grow and change rapidly. Mutations can lead to changes in the antigens on the surface of the tumour, and the immune system will no longer be able to recognise the tumour. Tumour cells secrete immunosuppressive cytokines or interfere with the effective presentation of tumour antigens on MHC (= major histocompatibility complex, a multi-gene family of cell surface proteins that bind and present antigens to the adaptive immune system) molecules. A process known as antigen shedding, which is the ability of tumour cells to shed antigens from the outer cell membrane, has also been observed as an attack-evasion strategy. That said, some tumour-associated antigens have long been used as clinical tumour markers, including alpha fetoprotein (AFP; in liver cancer), which is expressed during foetal development, but is transcriptionally repressed shortly after birth. However, it is re-expressed in HCC patients with higher than normal AFP concentrations.

Overstrained immune system

It is assumed that one consequence of the interactions between the immune system and cancer cells is that the CD8+ T killer cells become exhausted and shut off if too much antigen is present. The CD8 molecule on the surface of cytotoxic T cells serves as co-receptor for the T cell receptor and is responsible for the recognition and binding of pathogens or mutated cancer proteins. Exhaustion and unresponsiveness of CD8+ T cells due to chronic stimulation causes the cells to express the inhibitory receptors PD-1 (programmed cell death receptor 1) and CTLA1 (cytotoxic T-lymphocyte antigen 4). These two receptors play an important role in down-regulating the immune response when the system becomes too active. They inhibit T-cell activation, reduce autoimmunity and promote self-tolerance. In liver cancer, these receptors are important markers of T-cell depletion. HCC is characterised by quite a complex immunological scenario, which is in part due to the physiological function of the liver. On the one hand, the organ needs immune response mechanisms that eliminate pathogens while, on the other, it needs mechanisms that help it tolerate substances (antigens) from the gastrointestinal tract, which would otherwise lead to excessive immune reactions. That said, this is the reason why patients with HCC generate weaker immune responses against cancer cells than patients with malignant melanoma and others.

So, what happens in patients with HCC? The answer is that the tumor defends itself against being recognised, and the immune system in the liver becomes dysfunctional. Thimme and his team are therefore focusing on ways to strengthen weakened factors of the immune system in order to elicit a stronger immune response and hence improve HCC therapy outcome. Good results have already been achieved in the treatment of malignant melanoma with so-called checkpoint inhibitors (anti-PD-1 and anti-CTLA4) that were used to inhibit the inhibitory receptors PD-1 and CTLA-4. Similar studies are currently underway to assess their effect in HCC treatment. "These checkpoint inhibitors reverse the inhibition and the T cells start working again," Thimme says, adding that "HCC also needs to be treated with traditional approaches because the checkpoint inhibitors only lead to a partial recovery of the immune system. "HCC remains a difficult disease to cure and the tumour is probably clever enough to always have something up its sleeve to help it escape the human immune system," he concludes.