Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

Significance Patients suffering from hematologic malignancies might have no alternative to eliminating their morbid immune system. Although lethal irradiation or chemotherapy largely eradicates tumor cells, it also destroys the hematopoietic system, which necessitates transplantation of bone marrow stem cells from a healthy donor. T cells within the graft attack remaining tumor cells. This graft-versus-leukemia (GvL) effect is highly appreciated, because it prevents tumor relapses. Coevally, however, T cells attack nonmalignant tissue of the host with life-threating consequences called graft-versus-host disease (GvHD). We found that absence of the transcription factors NFAT (nuclear factor of activated T cells) in T cells prevents harmful GvHD, but preserves the valuable GvL. Therefore, instead of broad immune suppression, we propose to target NFAT specifically during allogenic stem cell transplantation.