Mutant calreticulin-driven myeloproliferative neoplasms favour the emergence of TIGIT-positive NK cells

Myeloproliferative neoplasms (MPNs) are chronic diseases characterized by an excessive production of myeloid blood cells. Janus kinase ( JAK2 ) V617F is the most common mutation in MPNs but a substantial proportion of patients harbour calreticulin ( CALR ) mutations—an attractive target for emerging immunotherapies. Natural killer (NK) cells have a central role in the elimination of malignant cells, but NK cells of MPN patients have reduced activity. Thus, reactivating their function might improve the disease outcome. Here, we demonstrate that NK cells from a CALR -mutant mouse model exhibit normal maturation but enhanced degranulation. Consistently, NK cells from CALR -mutant patients exhibit preserved degranulation ability, exceeding that observed in JAK2 -mutant patients. Notably, NK cells from CALR -, but not JAK2 -mutant patients express high levels of the immune checkpoint TIGIT possibly due to increased abundance of immunomodulatory proteins in the plasma. Moreover, CD34⁺ cells from MPN patients express elevated levels of the TIGIT ligand CD112. TIGIT blockade results in reduced platelet numbers in a transplant mouse model. These findings suggest that NK cells in CALR -mutant MPNs are activated but functionally constrained when encountering TIGIT ligand–expressing target cells, providing a strong rationale for exploring TIGIT blockade to restore NK-cell immunity in this disease subset.