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. 2019;59(1):1-16.
doi: 10.3960/jslrt.19003.

High TNFRSF14 and low BTLA are associated with poor prognosis in Follicular Lymphoma and in Diffuse Large B-cell Lymphoma transformation

Joaquim Carreras, Armando Lopez-Guillermo, Yara Yukie Kikuti, Johbu Itoh, Miyaoka Masashi, Haruka Ikoma, Sakura Tomita, Shinichiro Hiraiwa, Rifat Hamoudi, Andreas Rosenwald, Ellen Leich, Antonio Martinez, Giovanna Roncador, Neus Villamor, Lluis Colomo, Patricia Perez, Noriko M Tsuji, Elias Campo, Naoya Nakamura

High TNFRSF14 and low BTLA are associated with poor prognosis in Follicular Lymphoma and in Diffuse Large B-cell Lymphoma transformation

Joaquim Carreras et al. J Clin Exp Hematop. 2019.

Abstract

The microenvironment influences the behavior of follicular lymphoma (FL) but the specific roles of the immunomodulatory BTLA and TNFRSF14 (HVEM) are unknown. Therefore, we examined their immunohistochemical expression in the intrafollicular, interfollicular and total histological compartments in 106 FL cases (57M/49F; median age 57-years), and in nine relapsed-FL with transformation to DLBCL (tFL). BTLA expression pattern was of follicular T-helper cells (TFH) in the intrafollicular and of T-cells in the interfollicular compartments. The mantle zones were BTLA+ in 35.6% of the cases with similar distribution of IgD. TNFRSF14 expression pattern was of neoplastic B lymphocytes (centroblasts) and "tingible body macrophages". At diagnosis, the averages of total BTLA and TNFRSF14-positive cells were 19.2%±12.4STD (range, 0.6%-58.2%) and 46.7 cells/HPF (1-286.5), respectively. No differences were seen between low-grade vs. high-grade FL but tFL was characterized by low BTLA and high TNFRSF14 expression. High BTLA correlated with good overall survival (OS) (total-BTLA, Hazard Risk=0.479, P=0.022) and with high PD-1 and FOXP3+Tregs. High TNFRSF14 correlated with poor OS and progression-free survival (PFS) (total-TNFRSF14, HR=3.9 and 3.2, respectively, P<0.0001), with unfavorable clinical variables and higher risk of transformation (OR=5.3). Multivariate analysis including BTLA, TNFRSF14 and FLIPI showed that TNFRSF14 and FLIPI maintained prognostic value for OS and TNFRSF14 for PFS. In the GSE16131 FL series, high TNFRSF14 gene expression correlated with worse prognosis and GSEA showed that NFkB pathway was associated with the "High-TNFRSF14/dead-phenotype".In conclusion, the BTLA-TNFRSF14 immune modulation pathway seems to play a role in the pathobiology and prognosis of FL.

Keywords: BTLA; Follicular lymphoma; TNFRSF14 (HVEM); immune microenvironment; transformed follicular lymphoma.

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Conflict of interest statement

CONFLICT OF INTEREST: The authors have no conflict of interest to declare.

Figures

Fig 1
Fig 1
Immunohistochemical expression of BTLA in FL. A, Low BTLA expression in FL in all compartments. B, High BTLA expression both in the follicular and interfollicular compartments. C, Low BTLA expression in the follicular area, with a follicular T helper cell (TFH) pattern. D, High follicular BTLA expression (+weak staining of B cells, phenomena often seen in the high BTLA expression cases). E.1, BTLA+mantle zone and E.2, same area stained with anti-IgD antibody. F, BTLA expression is very low in transformed FL to Diffuse Large B-cell Lymphoma (tFL). G, Double immunofluorescence combined with peroxidase-DAB-based in reactive tonsil staining using confocal microscopy with volume rendering between BTLA (HRP-DAB-based IHC, yellow), PD-1 (red) and FOXP3 (green). The staining shows that in the germinal centers BTLA is identifying PD-1+follicular T helper cells (FTH). Original magnification of Figures A and B is 100X, the rest are 400X (Olympus BX53).
Fig 2
Fig 2
Immunohistochemical expression of TNFRSF14 (HVEM) in FL. The TNFRSF14 expression was analyzed first in reactive tonsil. A.1, Reactive tonsil, double immunohistochemistry between PAX5 (DAB, brown) and TNFRSF14 (red) shows that neoplastic B lymphocytes (centroblasts) are TNFRSF14 positive. A.2, Double immunohistochemistry between CD21 (DAB, brown) and TNFRSF14 (red) shows how TNFRSF14+B lymphocytes (mainly centroblasts) are surrounded by a network of CD21+follicular dendritic cells (FDC). A.3, MITF+cells with morphology of FCD and macrophage (red color, nuclear staining) are surrounded by TNFRSF14+cells. B, Low frequency of TNFRSF14+cells in FL (B.1 400X, B2, magnified inset). C.1, High frequency of TNFRSF14+cells (C.2, inset). D.1, transformed FL to DLBCL (tFL) with high TNFRSF14 expression (D.2, inset).
Fig 3
Fig 3
Overall survival of BTLA, FOXP3 and PD-1. High BTLA expression, either follicular, mantle, interfollicular and total correlated with good OS (P<0.05). Same results were found for total FOXP3 and follicular PD-1. Of note, BTLA did not correlate with the PFS.
Fig 4
Fig 4
Overall survival and progression free survival of TNFRSF14. High TNFRSF14 expression associated with poor prognosis in FL either in the follicular, interfollicular and total compartments, for both OS and PFS (P<0.001).
Fig 5
Fig 5
Overall survival and progression free survival of BTLA and TNFRSF14 on the rituximab-treatment cases. The prognostic relevance of BTLA and TNFRSF14 was maintained when we re-analyzed only the rituximab-treated patients (RCHOP and RCHOP-like).
Fig 6
Fig 6
Gene expression analysis of TNFRSF14 in FL. At RNA level, high TNFRSF14 associated with worse OS using the LLMPP FL GSE16131 series. The GSEA plot showed an enrichment of the NFkB pathway towards the FL “dead - high TNFRSF14 phenotype”. Protein-protein interaction analysis of the TNFRSF14-NFkB pathway with molecular actions were as follows: green (activation), red (inhibition), blue (binding), pink (posttranslational modification).
Fig 7
Fig 7
TNFRSF14 (HVEM) and BTLA pathway and the immune microenvironment in FL. This Figure shows the TNFRSF14 and BTLA expression in the FL microenvironment and the possible effect of the engagement of the ligands and receptors, either activating or inhibiting. Our hypothesis is that the resulting nonequilibrium of factors is what triggers the development and/or progression of FL towards a poor prognosis and transformation to DLBCL. This Figure is based on our experimental results as well as other publications.,,-,-
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