HVEM loss drives B-cell proliferation and promotes a protumorigenic microenvironment.
Major finding: HVEM loss drives B-cell proliferation and promotes a protumorigenic microenvironment.
Mechanism: Loss of the HVEM–BTLA interaction drives BCR signaling and increases stroma-activating cytokines.
Impact: Immune cells can be modified to deliver anticancer proteins as a targeted therapeutic approach.
Somatic mutations of the tumor suppressor tumor necrosis factor receptor superfamily member 14 (HVEM, encoded by TNFRSF14), which frequently occur in follicular lymphomas (FL), disrupt the interaction between HVEM and the immune checkpoint protein B and T lymphocyte associated (BTLA), resulting in the inhibition of T-cell immune responses. To elucidate the role of HVEM in germinal center (GC) lymphomagenesis, Boice, Salloum, Mourcin, and colleagues evaluated the interaction between HVEM and BTLA in FLs. Genomic and immunohistochemical analyses of human FLs identified HVEM mutations in 28% (40 of 141) of patient samples and the mutually exclusive loss of either HVEM or BTLA expression in 73% (145 of 198) of patient samples. Depletion of B cell–specific Hvem or Btla in a genetically engineered mouse model of FL resulted in enhanced lymphomagenesis in Hvem-deficient mice and Btla-deficient mice compared to control mice. Further, the morphology and activated status of the B-cell receptor (BCR) signaling pathway in Hvem-deficient lymphomas and Btla-deficient lymphomas closely resembled those of GC FLs, and Hvem-deficient lymphomas exhibited increases in stroma-activating cytokines and follicular T helper cell infiltration compared to controls. The soluble HVEM ectodomain protein (solHVEM), which retains BTLA binding activity, inhibits activated BCR signaling in lymphoma B cells and partially reversed aberrant cytokine production by HVEM-deficient lymphoma B cells. Moreover, solHVEM ablated growth of BTLAhi lymphomas compared to BTLAlo lymphomas and controls, respectively, in vitro and in vivo. Anti-CD19 chimeric antigen receptor (CAR)–T cells modified to express and secrete solHVEM displayed greater antitumor efficacy than control anti-CD19 CAR-T cells against lymphomas in vivo. Taken together, these results provide new insights into the tumor suppressor function of HVEM by elucidating the BTLA-dependent mechanism by which HVEM inhibits BCR signaling and activation of the tumor microenvironment, and provide evidence that immune cells can be engineered for the local delivery of anticancer therapies.
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