BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination
Laurent Derré, Jean-Paul Rivals, Camilla Jandus, Sonia Pastor, Donata Rimoldi, Pedro Romero, Olivier Michielin, Daniel Olive, Daniel E. Speiser
Laurent Derré, Jean-Paul Rivals, Camilla Jandus, Sonia Pastor, Donata Rimoldi, Pedro Romero, Olivier Michielin, Daniel Olive, Daniel E. Speiser
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Research Article

BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination

Abstract

The function of antigen-specific CD8+ T cells, which may protect against both infectious and malignant diseases, can be impaired by ligation of their inhibitory receptors, which include CTL-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1). Recently, B and T lymphocyte attenuator (BTLA) was identified as a novel inhibitory receptor with structural and functional similarities to CTLA-4 and PD-1. BTLA triggering leads to decreased antimicrobial and autoimmune T cell responses in mice, but its functions in humans are largely unknown. Here we have demonstrated that as human viral antigen–specific CD8+ T cells differentiated from naive to effector cells, their surface expression of BTLA was gradually downregulated. In marked contrast, human melanoma tumor antigen–specific effector CD8+ T cells persistently expressed high levels of BTLA in vivo and remained susceptible to functional inhibition by its ligand herpes virus entry mediator (HVEM). Such persistence of BTLA expression was also found in tumor antigen–specific CD8+ T cells from melanoma patients with spontaneous antitumor immune responses and after conventional peptide vaccination. Remarkably, addition of CpG oligodeoxynucleotides to the vaccine formulation led to progressive downregulation of BTLA in vivo and consequent resistance to BTLA-HVEM–mediated inhibition. Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells, and appropriate immunotherapy may partially overcome this inhibition.

Authors

Laurent Derré, Jean-Paul Rivals, Camilla Jandus, Sonia Pastor, Donata Rimoldi, Pedro Romero, Olivier Michielin, Daniel Olive, Daniel E. Speiser

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Figure 3

Expression of HVEM and its ligands BTLA and LIGHT by melanoma cells; and BTLA-mediated functional inhibition of tumor antigen–specific BTLA+ CD8+ T cells.

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Expression of HVEM and its ligands BTLA and LIGHT by melanoma cells; and...
(A) Representative examples of BTLA, LIGHT, and HVEM expression by the melanoma cell lines Me 280, Me 261, and Me 290. Cells were stained with isotype control (open histograms) or with anti-HVEM, anti-BTLA, or anti-LIGHT mAb (filled histograms) (B) Relative expression of HVEM, BTLA, and LIGHT by melanoma cell lines, expressed as ratio fluorescence intensity (RFI), i.e., MFI with specific mAb/MFI with isotype control. Of 40 melanoma cell lines analyzed, 19 were highly positive (white dots), 7 weakly positive (gray dots), and 14 negative for HVEM expression (black dots). None of the melanoma cell lines expressed BTLA or LIGHT (black dots). (C) HVEM expression (in reddish brown) detected in paraffin-embedded tumor sections from 16 tumors of 14 melanoma patients. Examples show tumor tissues that were HVEM-negative, weakly positive (<10% HVEM+ tumor cells) or strongly positive (>50% positive tumor cells). Original magnification, ×200. (D) Melan-AMART-1/HLA-A*0201–specific CD8+ T cell clones (cl.) 618-45, 618-4, and 618-420 were stimulated by melanoma cell lines Me 275 and Me 290 (both Melan-A+, HLA-A*0201+, HVEM+). The graph shows fold increase in IFN-γ production by Melan-AMART-1–specific clones in the presence of blocking antibody BTLA-8.2, relative to isotype control antibody. IFN-γ production was determined by ELISA in supernatants of 24-hour cultures. BTLA expression by T cell clones was assessed by flow cytometry with BTLA-specific antibody (filled histograms) and isotype control (open histograms). GMFI is indicated in parentheses.