Austrian researchers identify potential immunotherapy target for CALR-mutant blood cancers

AUSTRIA—Researchers at Karl Landsteiner University of Health Sciences (KL Krems) have identified TIGIT, an immune-inhibiting receptor, as a potential treatment target for patients with a genetic form of myeloproliferative neoplasms (MPNs), following laboratory and animal model studies.

The international research team found that natural killer (NK) cells in patients with mutations in the calreticulin (CALR) gene retain much of their ability to attack abnormal cells.

However, an inhibitory molecular signal appears to restrict this immune response.

Blocking the signal improved the cells’ ability to destroy diseased cells in laboratory experiments and showed encouraging effects in an experimental disease model.

TIGIT limits immune cell activity

MPNs are chronic blood disorders in which the bone marrow produces excessive numbers of blood cells.

Depending on the subtype, patients may develop blood clots, bone marrow scarring or progress to acute myeloid leukaemia.

Although existing treatments help manage symptoms and complications, they rarely eliminate the underlying disease.

Genetic mutations influence how MPNs develop and respond to treatment. Among the most common are mutations affecting CALR and Janus kinase 2 (JAK2).

While previous research has established that MPNs can disrupt immune function, the effects of these mutations on the body’s natural cancer defences remain poorly understood.

To investigate this, researchers from KL Krems’ Department of Pharmacology compared NK cells from patients with CALR mutations with those carrying JAK2 mutations.

The analysis revealed that NK cells from JAK2-mutant patients showed signs of impaired function, while those from CALR-mutant patients retained their ability to release substances involved in destroying abnormal cells.

However, the latter group also showed elevated levels of TIGIT, a receptor that suppresses immune responses.

The researchers also found increased levels of CD112, a molecule that activates TIGIT, on blood-forming precursor cells from affected patients.

In addition, blood samples contained elevated concentrations of several immune-regulating proteins, suggesting that the disease simultaneously stimulates NK cells and activates mechanisms that restrict their activity.

Antibody treatment shows potential

The team investigated whether blocking TIGIT could restore the immune response.

Using a specific antibody against the receptor, researchers improved the ability of NK cells to destroy abnormal cells in laboratory experiments.

In an experimental model of CALR-mutant disease, the antibody treatment also showed a tendency to reduce elevated platelet counts, a characteristic feature of certain MPN subtypes.

“These results provide a rationale for investigating TIGIT blockade as an additional treatment option for patients with CALR-mutant disease,” said the study’s co-first authors, Associate Professor Agnieszka Witalisz-Siepracka and Theresa Harm.

The researchers noted that this approach could help patients’ immune systems control malignant cells rather than targeting the mutations directly.

The findings are preclinical and require validation in larger patient groups and further experimental studies.

However, TIGIT-targeting antibodies are already under clinical investigation in other cancer settings, providing an existing therapeutic development pathway that could support research into their potential application in blood cancers.

The study involved scientific and clinical collaborators from Austria, Germany and the United Kingdom.

Its findings also highlight the potential of patient-derived immune profiling to identify treatment targets and support the development of more selective immunotherapies for genetically defined blood cancers.

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