{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T04:55:20Z","timestamp":1781758520484,"version":"3.54.5"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T00:00:00Z","timestamp":1781740800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"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>\n                      Uveal melanoma has a marked tropism for the liver where immune tolerance facilitates metastatic progression and resistance to immunotherapy. Impaired CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell immunosurveillance is a central determinant of disease progression in uveal melanoma, yet the underlying mechanisms driving liver-mediated immune subpression and hepatic metastasis are not fully understood. Here, we investigate molecular pathways that regulated hepatic CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell function and evaluate clinical outcomes associated with liver-directed therapy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Expression of autotaxin (ATX), the expression responsible for generating lysophosphatidic acid (LPA), was evaluated in hepatic resident cell populations. ATX transcript levels were assessed in CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells isolated from hepatic metastases and compared with matched peripheral blood and healthy donor control. Antigen-specific effector CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells were used to characterize downstream signaling responses to LPA stimulation. Functional studies evaluating cytokine production during chronic antigen exposure were performed using CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells from  LPA receptor 5-deficient (\n                      <jats:italic>\n                        Lpar5\n                        <jats:sup>-\/-<\/jats:sup>\n                      <\/jats:italic>\n                      ) mice.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We identify the autotaxin-lysophosphatidic acid (ATX-LPA) axis as a prominent immunoregulatory pathway in the metastatic hepatic tumor microenvironment. ATX, the enzyme responsible for LPA production, is constitutively expressed by hepatic resident cells, is detectable on Kupffer cells and is associated with increased immunosubpressive markers. CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells isolated from hepatic metastasis in a patient with uveal melanoma display markedly elevated ATX transcripts compared to matched peripheral blood (&amp;gt;5 log\n                      <jats:sub>2<\/jats:sub>\n                      fold change) and healthy controls. Using antigen-specific effector CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells, we demonstrate LPA signaling induces low level, persistent ERK phosphorylation distinct from canonical antigen-induced TCR signaling. Genetic deletion of the LPA receptor 5 (\n                      <jats:italic>\n                        Lpar5\n                        <jats:sup>-\/-<\/jats:sup>\n                      <\/jats:italic>\n                      ) on CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells restores CD8 T cell percentages and cytokine function during persistent antigen stimulation in the presence of LPA.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings define an ATX-LPA mechanisms of dysfunctional ERK signaling that may contribute to hepatic immune subpression in uveal melanoma. We highlight this pathway as a rational therapeutic target alongside liver-directed clinical interventions.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1829486","type":"journal-article","created":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T04:35:25Z","timestamp":1781757325000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeting liver metastases in uveal melanoma: ATX-LPA mediated immunosuppression and novel therapeutic approaches"],"prefix":"10.3389","volume":"17","author":[{"given":"Jacqueline","family":"A. Turner","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Mayo Clinic College of Medicine and Science","place":["Rochester, MN, United States"]},{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"D\u2019Antonio","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heather N.","family":"Montane","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic College of Medicine and Science","place":["Rochester, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"MacBeth","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Katsnelson","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William A.","family":"Robinson","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard P.","family":"Tobin","sequence":"additional","affiliation":[{"name":"Division of Surgical Oncology, Department of Surgery, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasey L.","family":"Couts","sequence":"additional","affiliation":[{"name":"Division of Medical Oncology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetomir N.","family":"Markovic","sequence":"additional","affiliation":[{"name":"Department of Oncology, Mayo Clinic College of Medicine and Science","place":["Rochester, MN, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul M.","family":"Torres","sequence":"additional","affiliation":[{"name":"Department of Immunology and Microbiology, University of Colorado School of Medicine","place":["Aurora, CO, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/bjs\/znaf130","article-title":"Management of liver metastases from uveal 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