BTLA marks a less cytotoxic T-cell subset in diffuse large B-cell lymphoma with high expression of checkpoints

Immunotherapy results in lymphoma have been encouraging. Preclinical and clinical trials have proven checkpoint blockade, such as PD-1 antibody, as an effective treatment for lymphoma, including diffuse large B-cell lymphoma (DLBCL). Combination of checkpoint blockades has emerged as a new way to treat lymphoma; however, the status of checkpoint expression and their function in DLBCL have not been fully elucidated yet. In this study, we examined the expression of BTLA, PD-1, TIM-3, LIGHT, and LAG-3 in tumor microenvironmental T cells of DLBCL using flow cytometry and compared the cytotoxicity and differentiation status of BTLA⁺ and BTLA^- T-cells. We further characterized the relationship of STAT3 phosphorylation (p-STAT3) with BTLA expression. Our results suggest that BTLA⁺ T cells highly express other checkpoint molecules, including PD-1, TIM-3, LIGHT, and LAG-3. Moreover, high expression of BTLA is correlated with advanced stage of DLBCL. BTLA⁺ T cells have a less-differentiated phenotype, lower cytolytic function, and higher potential to proliferate compared with BTLA^- T cells. Taken together, our data provide the first evidence that increased BTLA predicts poor prognosis in patients with DLBCL, and blockade of BTLA with other checkpoints may potentially represent a new strategy for immunotherapy of DLBCL.