Two TANDEM Grants by the ISREC Foundation strengthen translational cancer research at the DBM
The ISREC Foundation has awarded TANDEM Grants to two research projects involving scientists and clinicians from the Department of Biomedicine (DBM). These projects address significant challenges in cancer treatment, such as overcoming immune evasion in acute myeloid leukemia and understanding why T cells lose their anti-tumor function in solid tumors. By bringing together complementary expertise from basic and clinical research, both projects reflect the translational approach at the heart of the TANDEM program.
Targeting immune evasion in acute myeloid leukemia
Prof. Petya Apostolova, clinician-scientist at the DBM and University Hospital Basel, and Prof. Nina Cabezas-Wallscheid from ETH Zurich will investigate how leukemia stem cells (LSCs) manipulate their metabolic environment to evade the immune system.
Acute myeloid leukemia (AML) is an aggressive cancer of the bone marrow. Despite intensive treatment, long-term survival remains poor, largely because therapy-resistant LSCs can persist and cause relapse. The researchers have identified a potential mechanism behind this resistance: LSCs alter the concentrations of specific metabolites in their surroundings. This metabolic environment can suppress macrophages and T cells in the bone marrow niche, potentially allowing LSCs to escape immune surveillance.
Leukemic stem cells are rare, and until recently we lacked tools sensitive enough to study them closely — so whether they leave a unique metabolic fingerprint on their environment has remained unclear. With new, highly sensitive metabolomics techniques and advanced cell culture models, we now want to define this fingerprint in patient samples and identify the immunosuppressive metabolites we could target to help eliminate leukemia.
Petya Apostolova
The project will investigate which metabolites are released by LSCs and how they influence immune cells in their environment. Using highly sensitive metabolomics technologies, the researchers can analyze metabolites released from as few as 5,000 LSCs. They will combine these approaches with patient samples and preclinical models to explore whether targeting LSC-derived immunosuppressive metabolites, together with standard chemotherapy, could help overcome immune evasion.
The collaboration combines Nina Cabezas-Wallscheid’s expertise in hematopoietic and leukemia stem cell metabolism with Petya Apostolova’s clinical and mechanistic expertise in AML and immunometabolism. The Basel team will lead patient recruitment and sample acquisition as well as experiments using LSC–T cell co-cultures and 3D human bone marrow niche models.
Understanding why T cells lose their function in tumors
A second TANDEM Grant brings together Dr. Grégory Verdeil from the University of Lausanne and Ludwig Institute for Cancer Research Lausanne, Prof. Kirsten Mertz, Professor of Pathology at the University of Basel, and Prof. Alfred Zippelius, Professor of Translational Oncology at the DBM. Their project investigates why T cells progressively lose their ability to attack cancer cells within tumors – a process known as T cell exhaustion.
The researchers will focus on NFAT5, a transcription factor that helps cells respond to environmental stress. Previous research suggests that NFAT5 becomes activated in T cells within tumors and contributes to their dysfunctional state. Its activity appears to be particularly high near necrotic tumor regions, where dying cancer cells alter the local environment. The team hypothesizes that this environmental stress activates NFAT5, thereby contributing to T cell exhaustion.
Tumors are highly heterogeneous tissues, and understanding not only which immune cells are present, but also where they are located and what surrounds them, can provide important biological information. We want to determine whether spatial patterns of NFAT5 activity are associated with T cell dysfunction and with the response of patients to therapy. If so, NFAT5 could potentially become a useful biomarker for treatment stratification.
Kirsten Mertz
Kirsten Mertz and her team will investigate whether this mechanism is relevant in patients with melanoma and non-small cell lung cancer. Using multiplex imaging and spatial tissue analysis, they will examine NFAT5 activity in patient tumors and its relation with T cell function and response to immunotherapy. If such an association can be demonstrated, NFAT5 could potentially serve as a biomarker to help identify which patients are more likely to benefit from treatment.
The project will also investigate whether temporary inhibition of NFAT5 could improve engineered T cell therapies, including CAR T cells and TCR-engineered T cells, by helping them retain their anti-tumor function after entering the challenging tumor environment.
At the DBM, Alfred Zippelius and senior scientist Karin Schäuble will explore another aspect of the same mechanism: whether NFAT5 can be targeted therapeutically. Antisense oligonucleotides have been developed that reduce NFAT5 expression, with initial preclinical experiments indicating improved tumor control. The researchers will now test this approach in melanoma and lung cancer models as well as patient-derived tumor material.
From a clinical perspective, we would like to better understand which patients are likely to respond to immunotherapy, but also how we can overcome resistance. NFAT5 is interesting because it may provide information about the state of the immune response and, at the same time, represent a possible therapeutic target.
Alfred Zippelius
The aim of this project is to bring these two aspects together.
Karin Schäuble
From mechanisms to better cancer therapies
Although the two projects focus on different cancers and biological mechanisms, they share a common goal: understanding how the tumor environment suppresses the immune response and using this knowledge to improve cancer treatment. One explores the metabolic interactions that allow LSCs to evade immune attack; the other investigates how environmental stress contributes to T cell dysfunction in solid tumors.
Both projects integrate basic biological insights, patient samples, clinical expertise, and translational approaches, uniting complementary disciplines to advance discoveries from the laboratory to clinical applications. This close collaboration between basic and clinical research is central to the ISREC Foundation’s TANDEM program and exemplifies the DBM's mission and vision.