Featured Lendület (Momentum) Researcher: Lajos Vince Kemény

Over the past decade and a half, the advent of immunotherapies has fundamentally changed the prognosis of many oncological diseases. This is particularly true for melanoma, which used to have a five-year survival rate of less than ten per cent in advanced stages. However, thanks to developments in immunotherapy, this rate has risen to over fifty percent, leading to a dramatic improvement in patient survival. It is no coincidence that research into the development of immunotherapies for oncology has been awarded a Nobel Prize. Nevertheless, the treatment of melanoma is far from being solved, as many patients continue to respond poorly to immunotherapy or become resistant to these treatments over time.

Research into “invisible” melanoma cells

“How to enhance the immunotherapeutic response in cancer patients, especially melanoma patients, is therefore a key question,” says Kemény, head of the Momentum research group.

“Melanoma cells often defend themselves against immunotherapies by eliminating their antigen presentation, making them essentially “invisible” to the immune system. The aim of our research is to explore this phenomenon and to investigate alternative therapeutic approaches to effectively treat the disease when the antigen presentation of tumour cells is inhibited.”

Vince Lajos Kemény

Antigens are molecules that can be recognised by individual cells of the immune system, triggering an immune response. Recognition often occurs because tumour cells present peptides on their surface that serve as antigens for the immune system. The presentation of these antigens on the surface of the cells is mediated by the major histocompatibility complex (MHC) proteins. However, tumour cells often attempt to avoid antigen presentation by inhibiting the release of MHC-I proteins into the cell membrane by various mechanisms, thus reducing the chance of recognition by the immune system.

An innovative approach

Members of the research team are looking for therapeutic targets that can sensitise tumour cells against the immune system, independently of antigen presentation. Certain cells of the immune system can fight tumour cells without presenting their antigens to them.

The Momentum team is therefore looking for drug-inhibitable targets in tumour cells that can sensitise these otherwise therapy-resistant cells to the immune system.

“In this research project, we are using a new technology that allows us to investigate the role of thousands of genes in the development of immune responses in tumour cells at genome scale in a preclinical mouse model. With this innovative approach, we can gain an accurate picture of how different genes in tumours influence the immune response, opening up the possibility of identifying new therapeutic targets and enhancing the response of tumours to immunotherapy interventions,” explains Kemény. “We combine this approach in an immunotherapy-resistant model of melanoma that we have created. So, overall, we are looking for new therapeutic targets to overcome immunotherapy-resistant tumours.”

The research team conducts experiments on special mouse models that serve as a melanoma model. In this tumour model, melanoma cells are unable to present antigens, but are nevertheless partially recognised by other immune cells. Thus, this model provides an ideal system for investigating whether immunotherapy against skin cancer can be made more effective by bypassing antigen presentation of melanoma cells. The research team plans to study thousands of genes that can be targeted by drugs, so that their inhibition can also block the functioning of the tumour. The researchers are paying special attention to ensuring that their findings are as likely as possible to be applied in clinical practice, that is, in patient care.

To improve the immune system

“In order to maximise translation, we are investigating therapeutic targets that offer potential interventions from both a scientific and practical point of view,” says Kemény. “In our melanoma model, we are knocking out [Editor’s note: disabling] thousands of genes at a time and investigating which of these genes help to kill melanoma cells. In other words, which genes support the effective functioning of the immune system by turning them off. Our long-term goal is that if we can identify targets whose attack promotes the destruction of melanoma cells that are incapable of antigen presentation, we can also identify immune cells that mediate this alternative defence independent of antigen presentation.” The literature suggests that natural killer (NK) cells, neutrophil granulocytes or macrophages may be key players in these cases. These studies may play a crucial role in better understanding the biology of melanoma and in mapping tumour cell-immune cell interactions.

Kemény said that although melanoma therapy has been one of the biggest success stories in oncology treatment in recent years, with significantly improved survival rates for patients, the incidence of the disease continues to rise worldwide and remains a major public health problem. The therapeutic successes achieved are mainly due to immune and targeted therapies, or a combination of the two.

Current research is focused on how to use these therapies at earlier and earlier stages of the disease to avoid tumour progression and metastases.

In view of the clinical relevance of these therapeutic areas, research to support the success of these immunotherapies and to enhance the immune response against tumour cells, including the work of the new Momentum research group, is of particular importance.