Putting the brakes on BTLA in T cell-mediated cancer immunotherapy

Abstract

Attenuating coinhibitory molecules for the treatment of cancer is gaining a great deal of attention as a strategy for immunotherapy. The B and T lymphocyte attenuator (BTLA, CD272) is a novel coinhibitory molecule structurally and functionally related to CTLA-4 and PD-1. A study in this issue of the JCI by Derré et al. reveals that BTLA is expressed on virus-specific human CD8+ T cells but is progressively downregulated after their differentiation from a naive to effector phenotype (see the related article beginning on page 157). Surprisingly, tumor-specific human CD8+ T cells continue to express BTLA even after their differentiation to an effector phenotype. Remarkably, vaccination of melanoma patients with CpG led to BTLA downregulation on tumor-specific human CD8+ T cells, concomitant with restoration of their functionality. We discuss these findings in the context of the expanding field of cosignaling molecules and their implications for T cell-based therapies for cancer.

Figure 1. The B7/CD28 family interactions and their function outcomes.

The B7/CD28 family members are characterized by their common immunologlobulin extracellular binding domains, and their signaling pathways are driven mainly by their intracellular, tyrosine-containing motifs. In addition to the specific antigen–dependent signal provided by the MHC-antigen complex to the TCR, the cell-surface interactions involving the B7/CD28 family of cosignaling molecules provide a second signal to T cells to enhance or inhibit the TCR signal, which influences the proliferative capacity and functional fate of the T cell. In addition to CD28 ligation by B7-1 and B7-2, T cell costimulation can be mediated by ligation of inducible costimulator (ICOS) via its ligand ICOS-L or can be mediated by ligation of the newly reported trim-like transcript 2 (TLT-2) via its ligand B7-H3. Also, in addition to CTLA-4, BTLA, CD160, and PD-1, which exert their effects via ligation by their respective ligands, is a new molecule referred to as butyrophilin/B7-like molecule (BTNL2), a coinhibitory molecule that mediates signaling of activator protein 1 (AP1) and nuclear factor of activated T cells (NFAT) via a ligand that remains elusive (as indicated by a question mark). Costimulatory interactions are shown in green, coinhibitory interactions in red. TREMR, triggering receptors expressed on myeloid cells receptor. Adapted with permission from Cell (21).

Figure 2. BTLA expression inhibits tumor-specific human CD8⁺ T cell function, which can be overcome by vaccination with CpG.

In this issue of the JCI, Derré et al. report that naive human CD8⁺ T cells express high levels of the coinhibitory molecule BTLA on their surface. They find that BTLA can inhibit the function of tumor-specific human CD8⁺ T cells. In vivo, vaccination of melanoma patients with CpG dampened this inhibition, at least in part, by downregulating BTLA. (A) The surface expression of BTLA is gradually downregulated during differentiation of virus-specific human CD8⁺ T cells from a naive (CCR7⁺CD45RA⁺) to an effector cell phenotype (CCR7^dimCD45RA^–). These differentiated cells produce high amounts of IFN-γ. (B) The surface expression of BTLA is maintained on tumor Melan-A^Mart-1–specific human CD8⁺ T cells from patients vaccinated with conventional peptide vaccination consisting of a Melan-A_26-35 peptide and incomplete Freund’s adjuvant (IFA) even after their differentiation to an effector phenotype, and this is associated with impaired functionality, as indicated by their reduced capacity to produce IFN-γ. (C) The vaccination of melanoma patients with the TLR agonist CpG led to progressive BTLA downregulation on tumor Melan-A^Mart-1–specific human CD8⁺ T cells and resistance to BTLA-HVEM–mediated functional inhibition and robust production of IFN-γ. These data not only underscore the therapeutic potential of CpG but also reveal the clinical importance of the BTLA pathway.

Figure 3. Models of interaction among HVEM, BTLA, CD160, and LIGHT and their various functional effects on tumor-specific human CD8⁺ T cells.

BTLA, CD160, and LIGHT are differentially expressed on tumor-specific CD8⁺ T cells, and depending on their expression, they can mediate distinct outcomes: immune tolerance or effective immunity against tumor targets. Three potential interactions are shown. Left: If BTLA or CD160 is expressed and LIGHT expression is either low or absent, the coinhibitory BTLA-CD160-HVEM complex will be dominant, resulting in negative regulation of the tumor-specific CD8⁺ T cell by the human tumor. Middle: If LIGHT, BTLA, and CD160 are all expressed, they might form a complex with HVEM. This could trimerize HVEM, resulting in positive or negative regulation of the T cell by the tumor. Right: If LIGHT is expressed with little to no BTLA or CD160, the tumor-specific T cells receive a positive signal from the HVEM-expressing tumor, resulting in robust functional activation of the tumor-specific T cell. Thus, attenuation of BTLA via either CpG or antibody blockade might augment T cell–mediated immunotherapy for cancer. Potent tumor-specific T cell responses are mediated with conventional vaccination and CpG, which downregulates BLTA expression on T cells, as revealed by new findings reported by Derré et al. (9) and as represented in the right panel. Adapted with permission from Trends in immunology (22).