The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to γδ T-cell cytotoxicity

© 2010 by The American Society of Hematology
On the path to successful immunotherapy of hematopoietic tumors, γδ T cells offer great promise because of their human leukocyte antigen (HLA)–unrestricted targeting of a wide variety of leukemias/lymphomas. However, the molecular mechanisms underlying lymphoma recognition by γδ T cells remain unclear. Here we show that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to γδ T cell–mediated cytolysis. Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all Vγ9+ T cells, significantly inhibits lymphoma cell killing. Specific loss-of-function studies demonstrate that the role of ULBP1 is nonredundant, highlighting a thus far unique physiologic relevance for tumor recognition by T cells. Importantly, we observed a very wide spectrum of ULBP1 expression levels in primary biopsies obtained from lymphoma and leukemia patients. We suggest this will impact on the responsiveness to γδ T cell–based immunotherapy, and therefore propose ULBP1 to be used as a leukemia/lymphoma biomarker in upcoming clinical trials.
This work was distinguished with the Pfizer Award for ClinicalResearch 2009. This work was further supported by Fundação para a Ciência e Tecnologia (PTDC/SAU-MII/71662/2006) and Fundação Calouste Gulbenkian (SDH Oncologia 2008; Projecto 99293). L.F.M. is a Young Investigator from the Human Frontier Science Program and was supported by Fundação Luso-Americana para o Desenvolvimento and Fundação para a Ciência e Tecnologia (FCT; PTDC/SAU-MII/69280/2006 and PTDC/SAU-MII/78333/2006). T.L. and D.V.C. received PhD fellowships (47342/2008 and 37898/2007) from FCT.