{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T05:07:50Z","timestamp":1789103270107,"version":"build-2803163510"},"reference-count":71,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T00:00:00Z","timestamp":1789084800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI048073, AI067890, AI49237"],"award-info":[{"award-number":["AI048073, AI067890, AI49237"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["CA164679, CA177322"],"award-info":[{"award-number":["CA164679, CA177322"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["AHA-14BGIA20380277"],"award-info":[{"award-number":["AHA-14BGIA20380277"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003185","name":"National Psoriasis Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100003185","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Somatic mutations can rewire tumor\u2013immune interactions to favor cancer progression. Here, we define the functional impact of missense mutations in Herpesvirus entry mediator (HVEM, TNFRSF14), a receptor frequently altered in lymphoma and melanoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We first assessed binding interactions between cell-expressed HVEM proteins containing mutations identified in human B cell lymphoma and its ligands LIGHT (TNFSF14), B and T lymphocyte attenuator (BTLA), and CD160. We next assessed the capacity for these ligands in a soluble or membrane expressed format to engage these mutant HVEM receptors and activate NF-\u03baB signaling using luciferase assays. We additionally used NK92 cells in cytotoxicity assays with K562 and JVM13 target cells expressing these HVEM mutants to compare wild-type and mutant HVEM costimulation of NK cell lysis. We used proteomic analysis to identify BTLA and CD160 interacting proteins in NK92 and Jurkat cells, and phospho-proteomic analysis to identify signaling pathways activated by these receptors. We used a mouse model of B cell lymhoma expressing ovalbumin (TBL-OVA) and a mouse model of melanoma (B16) to assess how HVEM expression in these tumors regulated their expansion\n                      <jats:italic>in vivo<\/jats:italic>\n                      . Additionally, we used OT1 transgenic CD8+ T cells that recognize TBL-OVA cells and were derived from wild-type, Btla-deficient, or Cd160-deficient animals to assess the role of BTLA and CD160 in regulating anti-tumor responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that HVEM mutations identified in human B cell lymphoma cluster in the extracellular domain. These mutants selectively disrupt BTLA and CD160 binding, and showed weaker activation of NF-\u03baB in response to ligand binding compared to wild-type HVEM. These mutants also showed reduced costimulation of NK92 lytic function compared to wild-type HVEM. Proteomics revealed that BTLA engagement suppresses interferon signaling, whereas CD160 regulates MYC pathway activity. Functionally, HVEM expression and BTLA activation restrained growth of TBL-OVA tumors\n                      <jats:italic>in vivo<\/jats:italic>\n                      , while CD160 was required for optimal natural killer (NK) and tumor-specific CD8\u207a T cell responses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our data illustrate an immuno-evasion strategy used by lymphoma to interrupt HVEM-activated inhibitory signaling in cis, and CD160 costimulatory signaling in trans, demonstrating the pressure to acquire HVEM mutations. The HVEM network thus plays a critical role in regulation of anti-tumor immunity, making it an attractive target for clinical intervention in cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1914960","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:33:50Z","timestamp":1789101230000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Mutant HVEM in lymphoma disrupts BTLA and CD160 regulation of anti-tumor signaling"],"prefix":"10.3389","volume":"17","author":[{"given":"Wai Wai","family":"Lin","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah","family":"Huang","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Balmert","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Bjordahl","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian C.","family":"Ware","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aref","family":"Moshayedi","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carl F.","family":"Ware","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford Burnham Prebys Medical Discovery Institute","place":["La Jolla, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John R.","family":"\u0160ed\u00fd","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Sanford 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