Follicular lymphoma (FL) is among the most common and incurable forms of indolent B cell lymphoma. Somatic mutations that disrupt the HVEM (TNFRSF14) receptor gene in 28% of FL and include frequent homozygous lesions. The HVEM receptor interacts with the activating LIGHT and the inhibitory BTLA (B- and T- lymphocyte attenuator) receptors on B and T cells. Exactly, how HVEM mutations contribute to FL development is unknown. Here we show that the immune cell receptor HVEM (TNFRSF14) is a p53 response gene, and a frequent target of both somatic mutations, and recurrent chromosome 1p36 deletions in FL. Moreover, HVEM deficiency promotes FL development in vivo and establishes a favorable immune environment. Specifically, HVEM deficient lymphomas show an exaggerated activation of stromal components including follicular dendritic cells (FDCs) and increased recruitment of T follicular helper (TFH) cells that support B lymphocytes by secreting interleukins IL21 and IL4. Furthermore, HVEM loss stimulates B cell growth by disrupting an inhibitory BTLA (B and T Lymphocyte Attenuator) mediated signal. Notably, HVEM's tumor suppressor functions reside at the cell surface and extrinsic application of the HVEM ectodomain(P37-V202) can restore B cell growth control and block lymphoma growth in vivo. In addition, we demonstrate that CD19-specific, chimeric antigen receptor (CAR)-modified T cells that are further modified to constitutively secrete soluble HVEM ectodomain display significantly higher cytotoxicity against cancer B-cells with high BTLA expression in vivo.

Citation Format: Darin Salloum. HVEM (TNFRSF14) tumor suppressor in immune therapies of follicular lymphoma [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr PR03.