Co-inhibitory molecules in hematological malignancies

Co-inhibitory molecules

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.


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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