B and T lymphocyte attenuator (BTLA) has been identified as a novel co‐inhibitory receptor, expressed?by?a?majority?of?lymphocytes, and shows structural and functional similarities to CTLA‐4 and PD‐1. Because tumor‐infiltrating immune cells express multiple co‐inhibitory receptors, it is assumed that dual or triple blockade of co‐inhibitory receptors will enhance antitumor immunity. Indeed, combined blockade of the PD‐1/programmed death‐ligand 1 (PD‐L1) and CTLA‐4 pathways, and that of the PD‐1/PD‐L1 and lymphocyte activation gene 3 (LAG3) pathways, has been shown to enhance antitumor effects in a human clinical study and animal model studies. Thus, BTLA is expected to be a new target for interventions aimed at reversal of immune evasion and boosting of antitumor immunity in cancer patients. Expression of BTLA has been reported in B‐cell small lymphocytic lymphoma/chronic lymphocytic leukemia cells and gastric cancer cells. However, there are currently no data on the immunohistochemical expression of BTLA in the microenvironment of human tumors, and the clinical significance of BTLA expression in tumor‐infiltrating immune cells remains to be identified. It have also been reported that BTLA plays a critical role in the induction of peripheral T cell anergy in vivo. T cell anergy is also widely accepted as an important mechanism of tumor immune escape, although no previous studies have shown anergy cells in tissues. Casitas–B‐lineage lymphoma protein‐b (Cbl‐b), an E3 ubiquitin ligase, is critical for establishing the threshold for T cell activation and for induction of T cell anergy.
Oguro S, Ino Y, Shimada K, et al. Clinical significance of tumor‐infiltrating immune cells focusing on BTLA and Cbl‐b in patients with gallbladder cancer. Cancer Science. 2015;106(12):1750-1760.