BTLA elevation

High VISTA expression correlates with high BTLA, TIM-3, and TNFRSF14 checkpoint-related molecules and with poorer post-immunotherapy survival in pancreatic cancer, consistent with prior literature indicating that VISTA is prominently expressed on CD68+ macrophages in pancreatic cancers and requiring validation in larger prospective studies. Immunomic analysis may be important for individualized precision immunotherapy.

Our results demonstrated that BTLA KO significantly enhances the function of anti-CD30 CAR T cells in HVEM+ HL (Fig 1b), as assessed via tumor size (caliper) and CART30 expansion in the peripheral blood (flow cytometry)...Finally, we found that high BTLA RNA expression in tisagenlecleucel infusion products correlates with poor response to treatment in patients with DLBCL and FL (NCT02030834)... Our results reveal a critical role of the BTLA-HVEM axis in inhibiting CAR T cell function, and demonstrate that CRISPR-Cas9 deletion of BTLA leads to enhanced anti-tumor efficacy in multiple models of cancer. The key mechanism is the reduction of SHP-1/2 recruitment and the consequent increase in CAR T cell activation. The results of this study will be translated into a first in human clinical trial of BTLA-deficient CAR T cells for relapsed or refractory cancer.

High BTLA expression was found in a large number of tumor samples and significantly associated with other immune checkpoints with FDA-approved drugs. Furthermore, HVEM expression (ligand for BTLA) significantly correlates with high BTLA transcriptome levels. The BTLA/HVEM pathway has been associated with suppression of T cell-mediated anti-tumor activity and resistance to anti-PD-1 immunotherapy leading to poor clinical outcomes.