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.

BTLA marks a less-differentiated tumor-infiltrating lymphocyte subset in melanoma with enhanced survival properties

“…6,7 However, recent studies by other groups have found that BTLA may also promote cell survival by inducing a gene expression program similar to that induced by ICOS and CD28 costimulation. 8,9 Although BTLA has been characterized as a negative costimulatory molecule on T cells, a number of studies of human CD8 C T cells have shown that BTLA is constitutively expressed at a high level on na€ ıve CD8 C T cells and gradually downregulated during T-cell expansion and cytotoxic T lymphocyte (CTL) differentiation.…”

“…8,9 Although BTLA has been characterized as a negative costimulatory molecule on T cells, a number of studies of human CD8 C T cells have shown that BTLA is constitutively expressed at a high level on na€ ıve CD8 C T cells and gradually downregulated during T-cell expansion and cytotoxic T lymphocyte (CTL) differentiation. 6,10,11 A recent study suggested a close relationship between the expression of multiple inhibitory receptors (e.g., PD-1, TIM3, and LAG3) and antigen specificity, anatomic localization, and differentiation of CD8 C T cells in humans. 12 Therefore, it is likely that sustained BTLA expression marks a specific stage of differentiation in human CD8…”

Advances in cancer immunology and cancer immunotherapeutics

“…[110] Similarly, inhibitory receptors such as T-cell membrane protein 3, V-domain Ig suppressor of T cell activation, and B-and T-lymphocyte attenuator (BTLA) can be a potential target of checkpoint inhibitors. [111][112][113] Costimulatory molecules: Several agonists of costimulatory molecules expressed on the surface of T-cells or NK cells are under investigation. 4-1BB (CD137) agonist, urelumab, prevents T-cell apoptosis and promotes NK-mediated antibody-dependent cell cytotoxicity.…”

Immunothérapie des cancers

“…Par ailleurs, l'utilisation d'un anticorps anti-CTLA-4 se fonde justement sur la présence dans les tumeurs de lymphocytes T que l'expression de CTLA-4 -molécule de costimulation inhibitricea rendus anergiques [60]. D'autres molécules de costimulation inhibitrices (PD1, Tim-3, BTLA, etc., voir Glossaire) pourraient aussi contribuer à cette anergie des lymphocytes T, de même que la présence dans le microenvironnement tumoral de molécu-les suppressives (TGFβ, IL-10, IDO, voir Glossaire) (Figure 2) [45,46]. Le blocage de ces molécules par des anticorps ou des petites molécules chimiques est en cours d'évaluation (Figure 2).…”

“…Certaines cytokines (IL-7, IL-15, IL-21, etc.) ou certains adjuvants comme des ligands de TLR (CpG) pourraient également lever l'état d'anergie des lymphocytes T infiltrant les tumeurs ou les rendre réfractaires aux mécanismes d'immunosuppression [46]. Toutefois, l'action ambivalente de certaines cytokines ou agonistes des TLR rend difficile leur manipulation sur le plan clinique [47,48].…”