Tumor cell-intrinsic BTLA receptor inhibits the proliferation of tumor cells via ERK1/2

B and T lymphocyte attenuator (BTLA) is an immune checkpoint molecule that mediates the escape of tumor cells from immunosurveillance. Consequently, BTLA and its ligand-herpesvirus entry mediator (HVEM) are potentially immunotherapeutic targets. However, the potential effects of BTLA on tumor cells remain incompletely unknown. Here, we show that BTLA is expressed across a broad range of tumor cells. The depletion of BTLA or HVEM promotes cell proliferation and colony formation,which is reversed by re-overexpression of BTLA in BTLA knockout (KO) cells. On the contrary, overexpression of BTLA or HVEM inhibits tumor cell proliferation and colony formation. Furthermore, the proliferation of subpopulation with high BTLA is also significantly slower than that of the low BTLA subpopulation. Mechanistically, the coordination of BTLA and HVEM inhibits its major downstream ERK1/2 signaling pathway, thus preventing tumor cell growth. This study demonstrates that tumor cell-intrinsic BTLA/HVEM is a potential tumor suppressor and likely to have potential antagonist for immunotherapy, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment. Overall design: RNA-sequence of BTLA KD with control cells and the sorting subpopulations of high BTLA expression and low BTLA expression were performed and analysed by Berry Genomics (Beijing, China).