Key Points• BTLA-HVEM interaction negatively regulates the proliferation of LTgd.• BTLA-HVEM interaction appears as a new possible mechanism of immune escape by lymphoma cells.Vg9Vd2 cells, the major gd T-cell subset in human peripheral blood, represent a T-cell subset that displays reactivity against microbial agents and tumors. The biology of Vg9Vd2 T cells remains poorly understood. We show herein that the interaction between B-and T-lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) is a major regulator of Vg9Vd2 T-cell proliferation control. BTLA was strongly expressed at the surface of resting Vg9Vd2 T cells and inversely correlated with T-cell differentiation. BTLA-HVEM blockade by monoclonal antibodies resulted in the enhancement of Vg9Vd2 T-cell receptor-mediated signaling, whereas BTLA-HVEM interaction led to a decrease in phosphoantigen-mediated proliferation by inducing a partial S-phase arrest. Our data also suggested that BTLA-HVEM might participate in the control of gd T-cell differentiation. In addition, the proliferation of autologous gd T cells after exposition to lymphoma cells was dramatically reduced through BTLA-HVEM interaction. These data suggest that HVEM interaction with BTLA may play a role in lymphomagenesis by interfering with Vg9Vd2 Tcell proliferation. Moreover, BTLA stimulation of Vg9Vd2 T cells appears as a new possible mechanism of immune escape by lymphoma cells. (Blood. 2013;122(6):922-931)

Despite recent advances with monoclonal antibody therapy, chronic lymphocytic leukemia (CLL) remains incurable. Natural killer (NK) cells are potent antitumoral effectors, particularly against hematological malignancies. Defective recognition of B-CLL leukemic cells by NK cells has been previously described. Here, we deciphered the mechanisms that hamper NK cell-mediated clearance of B-CLL and evaluated the potential of NK cells as therapeutic tools for treatment of CLL. First of all, leukemic B cells resemble to normal B cells with a weak expression of ligands for NK receptors. Conversely, NK cells from B-CLL patients were functionally and phenotypically competent, despite a decrease of expression of the activating receptor NKp30. Consequently, resting allogeneic NK cells were unable to kill leukemic B cells in vitro. These data suggest that patients' NK cells cannot initiate a proper immune reaction due to a lack of leukemic cell recognition. We next set up a xenotransplantation mouse model to study NK-CLL cell interactions. Together with our in vitro studies, in vivo data revealed that activation of NK cells is required in order to control B-CLL and that activated NK cells synergize to enhance rituximab effect on tumor load. This study points out the requirements for immune system manipulation for treatment of B-CLL in combination with monoclonal antibody therapy.

Clear cell renal cell carcinomas (RCC) frequently display inactivation of von Hippel-Lindau (VHL) gene leading to increased level of hypoxia-inducible factors (HIF). In this study, we investigated the potential role of HIF2a in regulating RCC susceptibility to natural killer (NK) cell-mediated killing. We demonstrated that the RCC cell line 786-0 with mutated VHL was resistant to NK-mediated lysis as compared with the VHL-corrected cell line (WT7). This resistance was found to require HIF2a stabilization. On the basis of global gene expression profiling and chromatin immunoprecipitation assay, we found ITPR1 (inositol 1,4,5-trisphosphate receptor, type 1) as a direct novel target of HIF2a and that targeting ITPR1 significantly increased susceptibility of 786-0 cells to NK-mediated lysis. Mechanistically, HIF2a in 786-0 cells lead to overexpression of ITPR1, which subsequently regulated the NKmediated killing through the activation of autophagy in target cells by NK-derived signal. Interestingly, both ITPR1 and Beclin-1 silencing in 786-0 cells inhibited NK-induced autophagy and subsequently increased granzyme B activity in target cells. Finally, in vivo ITPR1 targeting significantly enhanced the NK-mediated tumor regression. Our data provide insight into the link between HIF2a, the ITPR1-related pathway, and natural immunity and strongly suggest a role for the HIF2a/ITPR1 axis in regulating RCC cell survival. Cancer Res; 74(23); 6820-32. Ó2014 AACR.