A new study from Karl Landsteiner University in Krems has pinpointed an immune pathway that could open treatment options for a specific subgroup of chronic blood cancers. Researchers found that natural killer (NK) cells, immune cells that target and destroy abnormal cells, remain functional in patients with CALR-mutant myeloproliferative neoplasms (MPNs). However, a molecular brake on these cells, triggered by the TIGIT receptor, limits their ability to attack diseased cells.
The discovery builds on existing knowledge that MPNs, disorders where the bone marrow overproduces blood cells, often lead to complications like clotting, bone marrow fibrosis, or progression to acute myeloid leukemia. Current treatments focus on managing symptoms rather than curing the disease. Genetic mutations, including those affecting the calreticulin (CALR) protein, influence how patients respond to therapy, but until now, little was understood about how these mutations affect immune function.
In the study, led by Professor Dagmar Stoiber-Sakaguchi, researchers compared NK cells from patients with CALR mutations to those with JAK2 mutations. While JAK2-mutant NK cells showed impaired function, CALR-mutant NK cells retained the ability to release cytotoxic substances. However, these cells have higher levels of TIGIT, a receptor that dampens immune responses. Further analysis revealed higher levels of CD112, a molecule that activates TIGIT, on blood-forming precursor cells from CALR-mutant patients.
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This suggests that while CALR mutations may stimulate NK cells, they also trigger signals that suppress their activity. To test whether this inhibition could be reversed, the team used an antibody to block TIGIT. In laboratory tests, the treatment restored the NK cells’ ability to destroy abnormal cells. In an experimental disease model, the antibody also reduced raised platelet counts, a common symptom in CALR-mutant MPNs.
The findings imply that targeting TIGIT could enhance the immune system’s ability to control CALR-mutant disease without directly attacking mutated cells. Unlike traditional therapies, this approach would leverage the patient’s own immune response. The study’s co-first authors, Associate Professor Agnieszka Witalisz-Siepracka and Theresa Harm, emphasized that the results are preliminary and require validation in larger patient groups.
Existing clinical trials for other cancers already investigate TIGIT-blocking antibodies, which could accelerate research into their use for MPNs. The study also suggests potential combinations with other immunotherapies. The work involved collaborators from Austria, Germany, and the UK, integrating molecular research, patient samples, and disease models to explore personalized treatment strategies.
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