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Clinical Trial
. 2016 Jul 7;128(1):72-81.
doi: 10.1182/blood-2015-10-679191. Epub 2016 Apr 21.

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

Eleni Kotsiou  1 , Jessica Okosun  1 , Caroline Besley  1 , Sameena Iqbal  1 , Janet Matthews  1 , Jude Fitzgibbon  1 , John G Gribben  1 , Jeffrey K Davies  1
Affiliations
Clinical Trial

TNFRSF14 aberrations in follicular lymphoma increase clinically significant allogeneic T-cell responses

Eleni Kotsiou et al. Blood. .

Abstract

Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graft-versus-host disease (GVHD). Next-generation sequencing has recently identified many new genetic lesions in follicular lymphoma (FL). One such gene, tumor necrosis factor receptor superfamily 14 (TNFRSF14), abnormal in 40% of FL patients, encodes the herpes virus entry mediator (HVEM) which limits T-cell activation via ligation of the B- and T-lymphocyte attenuator. As lymphoma B cells can act as antigen-presenting cells, we hypothesized that TNFRSF14 aberrations that reduce HVEM expression could alter the capacity of FL B cells to stimulate allogeneic T-cell responses and impact the outcome of AHSCT. In an in vitro model of alloreactivity, human lymphoma B cells with TNFRSF14 aberrations had reduced HVEM expression and greater alloantigen-presenting capacity than wild-type lymphoma B cells. The increased immune-stimulatory capacity of lymphoma B cells with TNFRSF14 aberrations had clinical relevance, associating with higher incidence of acute GVHD in patients undergoing AHSCT. FL patients with TNFRSF14 aberrations may benefit from more aggressive immunosuppression to reduce harmful GVHD after transplantation. Importantly, this study is the first to demonstrate the impact of an acquired genetic lesion on the capacity of tumor cells to stimulate allogeneic T-cell immune responses which may have wider consequences for adoptive immunotherapy strategies.

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Figures

Figure 1
Figure 1
Cell surface expression of HVEM is reduced on FL B cells with TNFRSF14 aberrations but expression of other molecules involved in antigen presentation is maintained. (A) Cell surface expression of HVEM (filled histograms) and isotype controls (open histograms) on FL B cells. Representative data are shown from patients with TNFRSF14 WT (left panel), single TNFRSF14 aberrations (middle panel), and dual TNFRSF14 aberrations (right panel). (B) Mean (± standard deviation) frequencies of HVEM+ cells, expressed as a percentage of FL B cells, for WT (n = 5), single aberration (n = 3), and dual TNFRSF14 aberration cases (n = 5). P value is for 2-tailed unpaired Student t test. (C) Surface expression of molecules involved in antigen presentation on FL B cells shown pre- and postactivation. The mean values are shown for 5 WT cases and 5 cases with dual TNFRSF14 aberrations. Error bars show standard deviation. There were no significant differences in the level of expression of CD58, MHC class I and II, CD80 or CD86 in WT FL B cells and FL B cells with dual TNFRSF14 aberrations either before or after in vitro activation (P > .05 in 2-tailed unpaired Student t test). MFI, mean fluorescence intensity; ns, not significant.
Figure 2
Figure 2
FL B cells with dual TNFRSF14 aberrations stimulate allogeneic T-cell activation more effectively than WT FL B cells. (A-B) Proportion of CD4+ and CD8+ T cells expressing the activation marker CD25 after primary (A; n = 7) and secondary (B; n = 5) allogeneic cocultures with WT FL B cells or FL B cells with dual TNFRSF14 aberrations. Horizontal bars and adjacent numbers represent median values and P values are for 2-tailed paired Student t tests. (C) Proportion of CD4+ T cells expressing the CD25hiCD127lo regulatory T-cell surface phenotype or (D) FOXP3 after primary (n = 4) and secondary (n = 4) allogeneic cocultures with WT FL B cells or FL B cells with dual TNFRSF14 aberrations. Mean values are shown and error bars represent standard deviation. P values are for 2-tailed paired Student t tests.
Figure 3
Figure 3
Frequencies of polyfunctional alloreactive T cells are increased after stimulation with FL B cells with dual TNFRSF14 aberrations. (A) Proinflammatory cytokines generated from allogeneic T cells after primary (n = 9) and secondary (n = 7) coculture with TNFRSF14 WT or dual TNFRSF14 aberration FL B cells. (B) Intracellular cytokine accumulation in allogeneic CD4+ and CD8+ T cells after primary (n = 8) and secondary (n = 7) coculture with FL B cells. Cytokine-positive cell frequencies are expressed as a percentage of T-cell subsets. (C) Surface CD107a+ cell frequencies (expressed as a percentage of T-cell subsets) in allogeneic CD4+ and CD8+ T cells after primary (n = 8) and secondary (n = 7) coculture with FL B cells. (A-C) Mean values ± standard deviation are shown. (D) Frequencies of allogeneic bifunctional T cells (CD107a+ and cytokine+) after primary allogeneic coculture with FL B cells. Horizontal lines depict median values. (E) Multifunctional allogeneic T-cell effectors after primary coculture with FL B cells. Cytokine-secreting populations within the alloreactive CD107a+ T-cell compartment are shown. Arcs show frequencies of T cells positive for CD107a, IFN-γ, TNF-α, and IL-2, and slices show effector populations with combined expression patterns of CD107a, IFN-γ, TNF-α, and IL-2. Mean frequencies from 7 independent experiments are shown. P values are for 2-tailed Student t tests throughout.
Figure 4
Figure 4
FL B cells with dual TNFRSF14 aberrations stimulate greater allogeneic T-cell proliferation than WT FL B cells. (A) Proliferation of allogeneic T cells measured by thymidine incorporation after primary (n = 7) and secondary (n = 6) coculture with TNFRSF14 WT or dual TNFRSF14 aberration FL B cells. Horizontal lines show median values. (B) Representative histograms of CFSE dye dilution in allogeneic T cells in secondary coculture with FL B cells. Numbers are proportions of proliferating cells. (C-D) Proportion of proliferating allogeneic CD4+ and CD8+ T cells after primary (C; n = 7) and secondary (D; n = 5) coculture with FL B cells. Horizontal lines show median values. (E) Proportion of proliferating CD4+ and CD8+ T cells after primary allogeneic coculture with TNFRSF14 WT FL B cells without and with exogenous BTLA antagonist or isotype control antibody. (F) Proportion of proliferating CD4+ and CD8+ T cells after primary allogeneic coculture (n = 3) with FL B cells with dual TNFRSF14 aberrations without and with exogenous BTLA agonist or isotype control antibody. Mean values ± standard deviation for 3 independent experiments are shown in panels E-F. P values are for 2-tailed Student t tests throughout. cpm, counts per minute.
Figure 5
Figure 5
TNFRSF14 aberrations in FL are associated with severe acute GVHD after AHSCT. (A) Schematic representation denoting TNFRSF14 status of purified FL B cells from lymph node biopsies from patients prior to allogeneic transplantation and occurrence of clinically significant acute GVHD (grades 2-4). Red text denotes patients whose acute GVHD was refractory to steroid therapy. (B) Cumulative incidence analysis of acute GVHD (grades 2-4) after allogeneic transplantation in FL patients with relapse/progression of lymphoma and death from other causes as competing risks. P value is for the Gray test. (C) Cumulative incidence analysis of death from acute GVHD (grades 2-4) after allogeneic transplantation in FL patients with relapse/progression of lymphoma and death from other causes as competing risks. P value is for the Gray test. NE, not evaluable.
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