B and T lymphocyte attenuator mediates inhibition of tumor-reactive CD8+ T cells in patients after allogeneic stem cell transplantation

• Published in: The Journal of immunology (1950) 2012-07, Vol.189 (1), p.39-49
• Main Authors: Hobo, Willemijn, Norde, Wieger J, Schaap, Nicolaas, Fredrix, Hanny, Maas, Frans, Schellens, Karen, Falkenburg, J H Frederik, Korman, Alan J, Olive, Daniel, van der Voort, Robbert, Dolstra, Harry
• Format: Article
• Language: English
• Subjects: Antibodies, Blocking - physiology; Antibodies, Blocking - therapeutic use; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - pathology; Cell Line, Tumor; Epitopes, T-Lymphocyte - metabolism; Gene Targeting - methods; Hematopoietic Stem Cell Transplantation; Herpesvirus; Humans; Immunologic Memory; Minor Histocompatibility Antigens - metabolism; Neoplasm Recurrence, Local - immunology; Neoplasm Recurrence, Local - pathology; Neoplasm Recurrence, Local - therapy; Receptors, Immunologic - antagonists & inhibitors; Receptors, Immunologic - immunology; Receptors, Immunologic - physiology; Receptors, Tumor Necrosis Factor, Member 14 - physiology; Tumor Cells, Cultured
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1102807

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.