{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:09:23Z","timestamp":1789711763413,"version":"4.0.1"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"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>Background<\/jats:title>\n                    <jats:p>T cell receptor (TCR)-engineered T cells target antigens presented on major histocompatibility complex (MHC) class I molecules. MHC class I expression is often low in childhood tumors such as neuroblastoma but can be stimulated by interferon gamma (IFN\u03b3). Chimeric antigen receptor (CAR) T cell effector function, including IFN\u03b3 production, is MHC class I-independent.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Aim<\/jats:title>\n                    <jats:p>We aimed to enhance neuroblastoma immunotherapy by combining CAR- and TCR-engineered T cells. Our strategy exploits CAR T cell-derived effector molecules, including IFN\u03b3, to increase tumor cell MHC class I expression and thereby enhance subsequent TCR T cell activity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      IFN\u03b3-mediated induction and persistence of MHC class I expression were analyzed in neuroblastoma cell lines by flow cytometry. Primary human T cells were engineered to express either a high-affinity TCR targeting the cancer testis antigen NY-ESO-1 or an L1CAM-targeted CAR. Cytotoxic activity of CAR and TCR T cells, applied alone or sequentially, was quantified against LAN-1 neuroblastoma cells using IncuCyte-based real-time killing assays. To model heterogeneous antigen expression, mixed tumor populations containing L1CAM-positive and CRISPR\/Cas9-generated L1CAM-knockout cells were analyzed.\n                      <jats:italic>In vivo<\/jats:italic>\n                      MHC class I upregulation was assessed in a human tumor xenograft model following treatment with human L1CAM-CAR T cells and in a syngeneic tumor model following treatment with GD2-CAR T cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      NY-ESO-1 TCR T cells alone showed limited cytotoxicity against LAN-1 cells\n                      <jats:italic>in vitro<\/jats:italic>\n                      , whereas L1CAM-CAR T cell pretreatment increased MHC class I expression and enhanced subsequent TCR-mediated killing. In tumor cells with heterogeneous CAR antigen expression, CAR T cell recognition of antigen-positive cells induced HLA-A*02 upregulation across the tumor population, enabling subsequent NY-ESO-1 TCR T cell recognition of cells not directly recognized by CAR T cells. Exploratory\n                      <jats:italic>in vivo<\/jats:italic>\n                      analyses further showed increased tumor MHC class I expression following CAR T cell treatment, providing preliminary evidence of CAR T cell-mediated inflammatory priming\n                      <jats:italic>in vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Sequential CAR- and TCR-engineered T cell therapy may help overcome limitations imposed by low MHC class I and heterogeneous antigen expression in neuroblastoma, supporting further investigation of this combinatorial strategy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1901504","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:39:31Z","timestamp":1789709971000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["CAR T cell-induced interferon gamma enhances MHC class I expression and sensitizes neuroblastoma to TCR-engineered T cell therapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Alice","family":"Vitali","sequence":"first","affiliation":[{"name":"Charit\u00e9 \u2013 University Medical Center Berlin, corporate member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin, Department of Paediatric Oncology and Haematology","place":["Berlin, Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennie","family":"Padlo","sequence":"additional","affiliation":[{"name":"Charit\u00e9 \u2013 University Medical Center Berlin, corporate member of Freie 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