Karl Landsteiner University tested TIGIT blockade in CALR-mutant blood neoplasms
Researchers restored the antitumor activity of NK cells against CALR-mutated blood neoplasm cells in preclinical tests.
An international team led by Karl Landsteiner University examined the molecular mechanisms suppressing immune responses in myeloproliferative neoplasms (MPNs) kl.ac.at
kl.ac.atkl.ac.atOpen source ↗. According to kl.ac.at, the preclinical study focused on the differences between patients carrying mutations in the calreticulin (CALR) gene and those with mutations in the JAK2 gene.
Myeloproliferative neoplasms lead to excessive blood cell production, causing risks of blood clots, bone marrow scarring, or progression to acute myeloid leukaemia. Existing therapies manage symptoms but rarely eliminate mutated cells. The authors evaluated NK cells from patients with different genetic profiles to determine why natural immune defenses fail to eliminate the abnormal clones.
Inhibitory receptors
The team found that while NK cells from JAK2-mutated patients exhibited impaired function, NK cells from CALR-mutated patients remained functional and capable of releasing cytotoxic substances kl.ac.at
kl.ac.atkl.ac.atOpen source ↗. However, their activity was suppressed by high surface levels of TIGIT, an inhibitory immune receptor. Furthermore, blood-forming precursor cells from these patients presented increased concentrations of CD112, a ligand that activates TIGIT, alongside elevated levels of circulating immunomodulatory proteins.
Preclinical blockade
To reverse this inhibition, researchers applied an antibody targeting TIGIT in laboratory experiments kl.ac.at
kl.ac.atkl.ac.atOpen source ↗. The intervention restored the capacity of NK cells to destroy abnormal cells in vitro. In an in vivo disease model harboring CALR mutations, the antibody treatment also showed a tendency to lower elevated platelet counts.
The findings remain at the preclinical stage and require validation in larger cohorts. The researchers noted that because TIGIT antibodies are already undergoing clinical trials for other oncological indications, investigating their application in CALR-driven MPNs could provide an additional immunotherapy pathway.
