CD8+ T cells that target tumors express much higher levels of an inhibitory molecule known as BTLA than human CD8+ T cells that target viruses, according to investigators at the Ludwig Institute for Cancer Research in Switzerland. Triggering BTLA on cancerous cells impaired their function.
The findings appear in an article titled “BTLA mediates inhibition of human tumor-specific CD8+ T cells that can be partially reversed by vaccination,” which was published in the December 28 issue of The Journal of Clinical Investigation (JCI).
BTLA (B and T lymphocyte attenuator) has been identified as a novel inhibitory receptor of antigen-specific CD8+ T cells. BTLA triggering leads to decreased antimicrobial and autoimmune T-cell responses in mice, but its functions in humans has been largely unknown.
The current research, led by Daniel E. Speiser, 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.
Further, persistently high levels of BTLA expression were detected on tumor-specific CD8+ T cells from melanoma patients who mounted spontaneous antitumor immune responses after conventional peptide therapy. More importantly, treating melanoma patients with both conventional peptide vaccination and a compound that decreased BTLA expression on tumor-specific CD8+ T cells restored the ex vivo functionality of the T cells.
Thus, BTLA activation inhibits the function of human CD8+ cancer-specific T cells. The authors therefore suggest that it might be useful to combine approaches to inhibit BTLA-mediated T-cell inhibition with conventional cancer vaccination strategies.