Study identifies potential immune target for CALR-mutant blood cancers
Researchers at Karl Landsteiner University (KL Krems) have identified an immune mechanism that could lead to new treatment options for certain chronic blood cancers. Their findings show that natural killer (NK) cells, which help the body eliminate cancer cells, retain much of their ability to attack abnormal cells in patients with a specific genetic form of myeloproliferative neoplasms (MPNs).
However, an inhibitory molecular signal appears to limit their activity. Blocking this signal restored the cells’ ability to destroy diseased cells in laboratory tests and showed encouraging results in an experimental disease model. The international research team believes the findings could support new immunotherapy approaches and help identify patients most likely to benefit.
MPNs are chronic blood disorders in which the bone marrow produces excessive numbers of blood cells. Depending on the subtype, patients may develop dangerous blood clots, bone marrow scarring or acute myeloid leukemia. Existing treatments can manage symptoms and complications but rarely eliminate the disease. Genetic mutations vary among patients and can influence treatment responses. One such mutation affects the protein calreticulin (CALR). Although immune dysfunction is known to occur in MPNs, little was understood about how CALR mutations affect the body’s natural defenses.
Researchers from KL Krems’ Department of Pharmacology investigated whether these differences could provide a basis for more targeted treatment. Led by Professor Dagmar Stoiber-Sakaguchi, head of the department, the team compared NK cells from patients with CALR mutations with those from patients carrying mutations in the JAK2 gene. The results showed that NK cells from JAK2-mutant patients had impaired function, while those from CALR-mutant patients retained their ability to release substances that help destroy abnormal cells. However, the CALR-mutant patients’ NK cells had unusually high levels of TIGIT, a receptor that suppresses immune responses. Further tests found increased levels of CD112, a molecule that activates TIGIT, on blood-forming precursor cells from affected patients.
The researchers also detected elevated levels of several immune-modulating proteins in their blood. Together, these findings suggest that CALR-mutant disease can stimulate NK cells while simultaneously activating signals that restrict their ability to attack cancer cells. To investigate whether this inhibition could be reversed, the researchers used an antibody to block TIGIT. Laboratory tests showed that the NK cells became more effective at destroying abnormal cells. Treatment with the antibody in an experimental model of CALR-mutant disease also showed a tendency to reduce the elevated platelet counts associated with this form of MPN.
Study co-first authors Associate Professor Agnieszka Witalisz-Siepracka and Theresa Harm said the results provide a basis for further research into TIGIT blockade as an additional treatment option for CALR-mutant disease. Rather than directly targeting mutated cells, this approach could help patients’ own immune systems control the disease more effectively. The findings are still at the preclinical stage and require confirmation through larger patient groups and further experiments.
However, antibodies targeting TIGIT are already being studied in clinical trials for other types of cancer, which could help inform future research into their use for MPNs. The findings also suggest that TIGIT blockade could be combined with other immunotherapies. The study involved scientific and clinical collaborators from Austria, Germany and the UK, combining molecular research, patient-derived samples and experimental disease models. KL Krems said this collaborative approach supports its research into the molecular mechanisms of cancer and the development of more personalized treatment strategies.
Category: Education
