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

Abstract

Key Points• TNFRSF14 gene aberrations, common in FL, increase the ability of lymphoma cells to stimulate allogeneic T-cell responses.• TNFRSF14 lesions were associated with increased acute GVHD supporting stratified transplantation approaches in the allogeneic setting.Donor T-cell immune responses can eradicate lymphomas after allogeneic hematopoietic stem cell transplantation (AHSCT), but can also damage healthy tissues resulting in harmful graftversus-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. (Blood. 2016;128(1):72-81)

Herpesvirus Entry Mediator and Ocular Herpesvirus Infection: More than Meets the Eye

“…Blockade of LIGHT-HVEM signaling has also been shown to increase the rate of survival of solid allografts, including pancreatic islets and cardiac transplants (141,142). Recently, lymphoma B cells from patients with mutations in the HVEM gene (TNFRSF14) were found to have increased alloantigen-presenting capacity in comparison to controls, corresponding to higher levels of GVHD in patients undergoing allogeneic hematopoietic stem cell transplantation (143). In murine experimental autoimmune uveitis (EAU), a model of human autoimmune conditions with ocular manifestations such as Behçet disease and sarcoidosis, HVEM was shown to increase disease severity by inducing pathogenic Th1-and Th17-type T cell responses (144).…”

Increased expression of TNFRSF14 indicates good prognosis and inhibits bladder cancer proliferation by promoting apoptosis

“…In a previous study, reduced TNFRSF14 expression was suggested to contribute to the pathobiology of classical Hodgkin lymphoma (8). Another previous study indicated that TNFRSF14 deficiency promotes development of follicular lymphoma in vivo and establishes a favorable immune environment (9). Cheung et al (10) reported that somatic TNFRSF14 mutations are associated with worse prognosis of follicular lymphoma.…”

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

“…BTLA and TNFRSF14 crosstalk regulates inhibition and costimulation of several key players of the immune system: BTLA functions as an inhibitory receptor in T lymphocytes 16 while the ligand TNFRSF14 produces proinflammatory signals via activation of NF-kappaB 17 and it is expressed by antigen presenting cells 18 . Interestingly, TNFRSF14 aberrations in FL increase clinically significant allogeneic T-cell responses 19 and in non-small cell lung cancer TNFRSF14 may contribute to the immune escape 20 …”