Co-inhibitory molecules in hematological malignancies
In advanced online publications of the Journal of Immunology and Blood, the research team led by Harry Dolstra (Laboratory of Hematology, Department of Laboratory Medicine, Nijmegen) have published a research article and a review on the influence of co-inhibitory molecules in suppressing T cell-mediated immunity against hematological malignancies.
In the research article by Willemijn Hobo and Wieger Norde et al., we investigated whether the co-inhibitory receptor BTLA (B and T lymphocyte attenuator) plays a role in T cell dysfunction after allogeneic stem cells transplantation (alloSCT). AlloSCT 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 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 co-inhibitory receptor programmed death-1 (PD-1) in suppressing MiHA-specific CD8+ T cell immunity (Norde et al., Cancer Res 2011; Hobo et al., Blood 2010). In this article, we investigated whether BTLA plays a similar role in functional impairment of MiHA-specific T cells after alloSCT. Besides PD-1, we observed high BTLA expression on MiHA-specific CD8+ T cells. Moreover, BTLA's ligand, herpes virus entry mediator (HVEM), was found constitutively expressed by leukemia, lymphoma, and multiple myeloma cells. Interference with the BTLA-HVEM pathway, using a BTLA blocking antibody, augmented proliferation of BTLA+PD-1+ MiHA-specific CD8+ T cells. We demonstrated that blocking of BTLA or PD-1 enhanced ex vivo proliferation of MiHA-specific CD8+ T cells in most alloSCT patients. Notably, in 3 of 11 patients, the effect of BTLA blockade was more prominent than that of PD-1 blockade. Together, these results demonstrate that BTLA-HVEM interactions impair MiHA-specific T cell functionality, providing a rationale for interfering with BTLA signaling in post-SCT immunotherapy.
In our review article in Blood, we discussed the role of co-inhibitory receptors in T cell immunity in hematological malignancies. In addition to our current research topics PD-1 and BTLA, a variety of other co-inhibitory molecules, including CTLA-4, LAG3, TIM-3 and CD200R, have been implicated in immune escape of cancer cells. We reviewed the influence of co-inhibitory pathways in suppressing autologous and allogeneic T cell-mediated immunity against hematological malignancies. Moreover, promising pre-clinical and clinical data of immunotherapeutic approaches interfering with negative co-signaling, either as monotherapy or in conjunction with vaccination strategies, are discussed. Numerous studies indicate that co-inhibitory signaling hampers the clinical benefit of current immunotherapies. Therefore, manipulation of co-inhibitory networks is an attractive adjuvant immunotherapeutic intervention for hematological cancers following standard treatment with chemotherapy and hematopoietic stem cell transplantation.
Taken together, we believe that interfering with co-inhibitory molecules will improve clinical benefit of immunotherapies against hematological malignancies in general, and more specifically our studies show that BTLA and PD-1 are attractive targets in alloSCT.
Articles:
Hobo W, Norde WJ, Schaap N, Fredrix H, Maas F, Schellens K, Falkenburg JH, Korman AJ, Olive D, van der Voort R, Dolstra H. B and T Lymphocyte Attenuator Mediates Inhibition of Tumor-Reactive CD8+ T Cells in Patients After Allogeneic Stem Cell Transplantation. J Immunol. 2012 May 25.
Norde WJ, Hobo W, van der Voort R, Dolstra H. Co-inhibitory molecules in hematological malignancies: targets for therapeutic intervention. Blood 2012 May 4.
Photo: (fltr) Willemijn Hobo, Wieger Norde, Frans Maas, Harry Dolstra and Robbert van der Voort
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