Unmasking "bad guys" in the immune system and turning them back into allies in the fight against cancer

Dr. Julia Krug receives a BZKF Young Scientist Fellowship of 100,000 euros for her innovative melanoma project

With her BZKF-funded project, Dr. Julia Krug from the University Hospital of Würzburg (UKW) aims to significantly increase the success rate of immunotherapies against malignant melanoma. For example, anti-PD-1 therapies fail in every second person affected. The natural scientist from the Schmieder research group (Immunodermatology) is investigating how immune-inhibiting macrophages ("bad guys") can be reprogrammed to overcome resistance. She has been awarded a one-year grant of 100,000 euros for her work.

Malignant melanoma, also known as "black skin cancer", is one of the most aggressive skin tumors. It has the highest metastasis rate and is the cause of death for around 3,000 people affected in Germany every year. Advances in treatment, such as modern immunotherapies, have improved the chances of survival for many of those affected. "But the immune checkpoint inhibitors don't work for every second patient," reports Dr. Julia Krug. The 35-year-old natural scientist from the Department of Dermatology at the University Hospital of Würzburg (UKW) would like to increase the success rate of immunotherapies. She has just been awarded the Young Scientist Fellowship of the Bavarian Center for Cancer Research(BZKF) for her project "Overcoming anti-PD-1 therapy resistance through targeted treatment of unresponsive melanomas with mifepristone bioconjugates".

"I was really pleased that my project was recognized in the local selection process. The fact that I was then also selected to present my work to a cross-location committee in a ten-minute presentation, and ultimately even won the fellowship, is a great appreciation of my work," says the award winner. In total, one project at each of the six Bavarian university hospitals will be funded with 100,000 euros for a period of one year.

New strategies for overcoming anti-PD-1 therapy resistance in malignant melanomas

Julia Krug goes into some detail about her project. In 2018, the Nobel Prize was awarded to two researchers who have revolutionized immunotherapies, in particular checkpoint inhibitors. James P. Allison discovered the immune-inhibiting molecule CTLA-4 and Tasuku Honjo discovered the receptor PD-1, which inhibits T-cell activation in a similar way to CTLA-4. If cancer cells carry the appropriate ligand on their surface, they can bind to the corresponding brake molecule on the immune cells and shut them down. Based on these fundamental findings, checkpoint inhibitors were developed, i.e. drugs that prevent cancer cells from pulling the "immune brake". This reactivates the patient's own immune system and allows it to perform its actual task of effectively fighting the cancer.

Reprogramming braking macrophages

To ensure that anti-PD-1 therapy works in more than half of patients, Julia Krug focuses on certain cells of the immune system: macrophages. The term is made up of the ancient Greek words makrós for "big" and phagein for "eat" and means "giant eating cells". They eat and digest everything that is potentially dangerous or superfluous for the body. They also recruit other immune cells to help in the fight against cancer. "However, there are also macrophages that have become 'bad guys' in the tumor microenvironment and slow down the immune system to such an extent that the tumor can continue to grow. We want to find these and convert them back to 'good guys'," explains Julia Krug.

Prof. Dr. Astrid Schmieder, head of the Immunodermatology working group at the UKW, had already done the groundwork and discovered various markers for the immunosuppressive macrophages. "We noticed a particular signaling pathway. If we can suppress this, the macrophages change their function and fight the tumor again," explains Astrid Schmieder, who is visibly proud of her successful postdoc. The two scientists are often referred to as the "power couple". What unites them, how they found their way into research and the passion with which they pursue their projects can be read in the portraits in the #WomenInScience series: University Hospital Würzburg: Research: Women in Science - Women researchers at the UKW

One cubic millimeter small cuboid from tumor sample

The mechanism of action that prevents activation of the ominous signaling pathway in macrophages has already proven itself in special mouse models. Julia Krug now wants to investigate it in human tissue samples. To this end, she is working with melanoma cell lines from the 1970s on the one hand and fresh surgical material on the other. The latter is cut into cubic millimeter cubes. This corresponds to the size of a grain of dust or one thirtieth of a drop of water. She then places these cuboids with her treated macrophages in a cell culture, adds inhibitors and sees within three days whether the material responds to the therapy. "And since we have a lot of cuboids from the tumor, we can test other mechanisms, methods and treatment strategies and predict the response rate," says Julia Krug enthusiastically about this "great tool".

However, a lot more research will be needed before this approach is standardized and the optimal treatment for each patient can be determined using a tiny tumour sample.

But Julia Krug, the new mother of a seven-month-old son, is full of energy. In January, her husband will take over her parental leave and thus the care work, so that she can hit the ground running again in the laboratory with the financial backing of the BZKF.

BZKF Young Scientist Fellowship

"The BZKF program is very important for Young Scientist Fellows. This is because the funding provides the young scientists with the necessary financial resources and, as clinician scientists, often also the necessary freedom for research," emphasizes Prof. Ralf Bargou. The Director of the Comprehensive Cancer Center Mainfranken and member of the BZKF Board of Directors is very keen to promote young scientists. When presenting the certificate, he congratulated Julia Krug on her well-deserved award. "Immuno-oncology research - both preclinical and clinical - is strongly represented in Würzburg and at WERA. There are many approaches to overcoming resistance, which is highly relevant in malignant melanoma in particular. I am looking forward to the results."

The Young Scientist Fellowship of the Bavarian Center for Cancer Research (BZKF) is a funding program for young scientists who want to carry out innovative projects in cancer research. The aim is to support promising young talents in Bavaria and enable them to implement their own translational research projects. These are projects that build a bridge between basic research and clinical application. The scholarship is aimed at medical scientists, clinician scientists, clinical trialists and young researchers from the fields of medicine, life sciences and natural sciences. The prerequisite is that the project is based at one of the BZKF locations in Bavaria. Funding of 100,000 euros per person for twelve months is provided, and six such fellowships are awarded per call for applications, one at each BZKF location. The selection takes place in a two-stage process: First, local selection processes take place at the six participating university hospitals. This is followed by a central final round with presentations to a cross-site committee, which also includes patient representatives and former fellows. In addition to financial support, the program offers integration into the BZKF's scientific network and support measures for long-term career development.

Text: KL / Science Communication

Link to the press release of the BZKF

Link to the #WomenInScience portrait of Julia Krug

To the Young Scientist Fellowship

Picture: Dr. Julia Krug receives the BZKF certificate from Prof. Dr. Ralf Bargou. © Annette Popp / UKW