B and T lymphocyte attenuator mediates inhibition of tumor-reactive CD8+ T cells in patients after allogeneic stem cell transplantation.
Allogeneic stem cell transplantation (allo-SCT) can cure hematological malignancies by inducing alloreactive T cell responses targeting minor histocompatibility antigens (MiHA) expressed on malignant cells. Despite induction of robust MiHA-specific T cell responses and long-term persistence of alloreactive memory T cells specific for the tumor, often these T cells fail to respond efficiently to tumor relapse. Previously, we demonstrated the involvement of the coinhibitory receptor programmed death-1 (PD-1) in suppressing MiHA-specific CD8(+) T cell immunity. In this study, we investigated whether B and T lymphocyte attenuator (BTLA) plays a similar role in functional impairment of MiHA-specific T cells after allo-SCT. In addition to PD-1, we observed higher BTLA expression on MiHA-specific CD8(+) T cells compared with that of the total population of CD8(+) effector-memory T cells. In addition, BTLA's ligand, herpes virus entry mediator (HVEM), was found constitutively expressed by myeloid leukemia, B cell lymphoma, and multiple myeloma cells. Interference with the BTLA-HVEM pathway, using a BTLA blocking Ab, augmented proliferation of BTLA(+)PD-1(+) MiHA-specific CD8(+) T cells by HVEM-expressing dendritic cells. Notably, we demonstrated that blocking of BTLA or PD-1 enhanced ex vivo proliferation of MiHA-specific CD8(+) T cells in respectively 7 and 9 of 11 allo-SCT patients. Notably, in 3 of 11 patients, the effect of BTLA blockade was more prominent than that of PD-1 blockade. Furthermore, these expanded MiHA-specific CD8(+) T cells competently produced effector cytokines and degranulated upon Ag reencounter. Together, these results demonstrate that BTLA-HVEM interactions impair MiHA-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-stem cell transplantation therapies.
Laboratory of Hematology, Department of Laboratory Medicine, Radboud University Nijmegen Medical Centre, Nijmegen Centre for Molecular Life Sciences, 6525 GA Nijmegen, The Netherlands.
Willemijn
W
Hobo
Wieger J
WJ
Norde
Nicolaas
N
Schaap
Hanny
H
Fredrix
Frans
F
Maas
Karen
K
Schellens
J H Frederik
JH
Falkenburg
Alan J
AJ
Korman
Daniel
D
Olive
Robbert
R
van der Voort
Harry
H
Dolstra
D019138:Antibodies, Blocking / Q000502:physiology / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D018390:Gene Targeting / Q000379:methods; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007156:Immunologic Memory; D015778:Minor Histocompatibility Antigens / Q000378:metabolism; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000473:pathology / Q000628:therapy; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000502:physiology; D014407:Tumor Cells, Cultured
D019138:Antibodies, Blocking; C482586:BTLA protein, human; D018984:Epitopes, T-Lymphocyte; D015778:Minor Histocompatibility Antigens; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14; C506028:TNFRSF14 protein, human