The MHC class Ib protein ULBP1 is a nonredundant determinant of leukemia/lymphoma susceptibility to gammadelta T-cell cytotoxicity.
On the path to successful immunotherapy of hematopoietic tumors, gammadelta 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 gammadelta T cells remain unclear. Here we show that the expression levels of UL16-binding protein 1 (ULBP1) determine lymphoma susceptibility to gammadelta T cell-mediated cytolysis. Consistent with this, blockade of NKG2D, the receptor for ULBP1 expressed on all Vgamma9(+) 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 gammadelta 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 gammadelta T cell-based immunotherapy, and therefore propose ULBP1 to be used as a leukemia/lymphoma biomarker in upcoming clinical trials.
Lança
Telma
T
Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisboa, Portugal.
Correia
Daniel V
DV
Moita
Catarina F
CF
Raquel
Helena
H
Neves-Costa
Ana
A
Ferreira
Cristina
C
Ramalho
José S
JS
Barata
João T
JT
Moita
Luís F
LF
Gomes
Anita Q
AQ
Silva-Santos
Bruno
B
D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism*; D001706:Biopsy; D045744:Cell Line, Tumor; D002986:Clinical Trials as Topic / Q000379:methods; D058851:GPI-Linked Proteins; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015458:Leukemia, T-Cell / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D034741:RNA, Small Interfering; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism*
D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D034741:RNA, Small Interfering; D016692:Receptors, Antigen, T-Cell, gamma-delta; C423231:ULBP1 protein, human