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

Exp Hematol. 2018 Apr:60:47-56.e1. doi: 10.1016/j.exphem.2018.01.003. Epub 2018 Feb 3.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / metabolism*
  • Disease-Free Survival
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / metabolism*
  • Lymphoma, Large B-Cell, Diffuse / mortality*
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Male
  • Neoplasm Proteins / metabolism*
  • Receptors, Immunologic / biosynthesis*
  • Survival Rate
  • T-Lymphocyte Subsets / metabolism*
  • T-Lymphocyte Subsets / pathology

Substances

  • BTLA protein, human
  • Biomarkers, Tumor
  • Neoplasm Proteins
  • Receptors, Immunologic