The Balancing Costimulation and Inhibition with BTLA – TNFRSF14 Pathway Predicts the Overall Survival in Follicular Lymphoma
Joaquim Carreras Esteban, Armando Lopez-Guillermo, Johbu Itoh, Yara Yukie Kikuti, Tomoki Kikuchi, Rifat Hamoudi, Giovanna Roncador, Noriko M Tsuji, Elias Campo, Naoya Nakamura. Tokai University, School of Medicine, Isehara, Kanagawa, Japan; Hospital Clinic, IDIBAPS, UB, Barcelona, Spain; UCL-Cancer Institute, London, United Kingdom; Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain; National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki, Japan
Background: Tumor microenvironment influences the behavior of follicular lymphoma (FL), but the specific role of inhibitory coestimulatory molecules are not well known yet. The aim of this study was to determine the impact of BTLA and its ligand, TNFRSF14, in the clinicobiological features and outcome of patients with FL.
Design: We examined samples from 100 patients (54M/46F; median age 56 years) at diagnosis, as well as in 9 patients at relapse with transformation to DLBCL, with a recently generated monoclonal antibody against BTLA and its ligand, TNFRSF14. Quantification was performed using computerized digital image analysis for BTLA and No cells/HPF for TNFRSF14. Additional analysis consisted of immunofluorescence with confocal microscopy and tridimensional imaging of the Germinal Center.
Results: BTLA expression was characteristic of TFH cells and positive in mantle zone while TNFRSF14 identified centroblasts and DCs (FDCs). Tridimensional analysis confirmed partial colocalization between BTLA and PD1 with FOXP3 independence. At diagnosis, the median numbers of BTLA and TNFRSF14-positive cells was 19.2% (range, 0.55% - 58.24%) and 46.7cells/HPF (range, 1 - 286.5), respectively. Higher numbers of TNFRSF14 correlated with poor performance status and high serum B2M. After a median follow-up of 6.2 years, patients with Total-BTLA-positive cells >8% (N=79) and ≤8% (N=21) had a 5-year OS of 80.5% and 51% (p=0.023). Patients with Total- TNFRSF14-positive cells >30 (N=46) and ≤30 (N=42) had an OS of 59.7% and 87% (p=0.005); and a PFS of 20.4% and 55.9% (p=0.007), respectively. Multivariate analysis showed that BTLA, TNFRSF14 and FLIPI maintained prognostic value for OS. At that time, transformed diffuse large B-cell lymphomas had lower percentage of BTLA-positive cells but higher TNFRSF14-positive cells than FL.
Conclusions: Low content of BTLA-positive cells or high number of TNFRSF14-positive cells predicted poor outcome of FL. Concordantly, transformed DLBCL also had a similar pattern of distribution of these cells.
*Prof. Nakamura and Campo contribuited equally to the study. Funded by HCP, AIST, JSPS, MEXT and Tokai UNV.
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 249, Tuesday Afternoon