{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T22:56:03Z","timestamp":1791327363623,"version":"4.3.1"},"reference-count":51,"publisher":"BMJ","issue":"2","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"unspecified","delay-in-days":10,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Medical Faculty, University of Zurich"},{"name":"Forschungskredit University of Z\u00fcrich"},{"name":"Comprehensive Cancer Center Z\u00fcrich project grant"},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["310030_192490"],"award-info":[{"award-number":["310030_192490"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,1,29]]},"published-print":{"date-parts":[[2026,2]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      ERBB2\/HER2 is overexpressed or mutated in ~15% of gastric cancers due to amplification or mutation of the\n                      <jats:italic>ERBB2<\/jats:italic>\n                      locus. While the tumor cell-intrinsic consequences of ERBB2 overexpression are well understood, much less is known about its effects on the tumor microenvironment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We have developed genetically engineered ectopic and orthotopic syngeneic models of organoid-based gastric cancer that have allowed us to study the tumor microenvironment of ErbB2-overexpressing tumors, using spectral flow cytometry, single cell RNA sequencing, and TCR repertoire sequencing. Interventions such as anti-Erbb2 and anti-PD1 antibody treatments were used as well.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We find that ErbB2 drives the infiltration of CD4\n                      <jats:sup>+<\/jats:sup>\n                      and CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cells, which express granzymes, FasL, and surface markers indicating chronic activation, and in the case of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cells, have undergone clonal expansion. The adoptive transfer of T-cells sorted from ErbB2-overexpressing tumors reduces the growth of ErbB2-expressing, but not control tumors in T-cell-deficient recipients. PD-1-specific checkpoint blockade synergizes with an ErbB2-targeting antibody to reduce the growth of ErbB2-expressing, but not control tumors. Mechanistically, ErbB2 overexpression results in micronuclei formation and the transcriptional activation of numerous interferon-responsive genes in vitro and in vivo; mice lacking the type I interferon receptor show higher engraftment rates and lower T-cell infiltration than wild-type controls.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The combined data indicate that ErbB2, perhaps by driving micronuclei formation, has immunogenic properties that manifest in the form of increased T-cell infiltration and expansion, which can be exploited therapeutically by combining PD1-directed checkpoint blockade with ErbB2-targeted therapy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012976","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T16:55:25Z","timestamp":1770828925000},"page":"e012976","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Genetically engineered ErbB2 overexpression sensitizes organoid-derived tumors to checkpoint inhibition in a syngeneic model of gastric cancer"],"prefix":"10.1136","volume":"14","author":[{"given":"Jiazhuo","family":"He","sequence":"first","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lydia","family":"Kirsche","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuzana","family":"Nascakova","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Manfredi","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, University of Z\u00fcrich and University Hospital Z\u00fcrich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2474-2159","authenticated-orcid":false,"given":"Chiara F","family":"Magnani","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology and Hematology, University of Z\u00fcrich and University Hospital Z\u00fcrich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanni","family":"Papa","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Azizi","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Leary","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Z\u00fcrich, Z\u00fcrich, Switzerland"},{"name":"Functional Genomics Center Z\u00fcrich, University of Z\u00fcrich and Federal Institute of Technology Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1368-8276","authenticated-orcid":false,"given":"Anne","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Institute of Molecular Cancer Research, University of Z\u00fcrich, Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"2026062607451784000_14.2.e012976.1","doi-asserted-by":"publisher","DOI":"10.1016\/0888-7543(89)90343-1"},{"key":"2026062607451784000_14.2.e012976.2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm1962"},{"key":"2026062607451784000_14.2.e012976.3","doi-asserted-by":"publisher","DOI":"10.5858\/2010-0454-RAR.1"},{"key":"2026062607451784000_14.2.e012976.4","doi-asserted-by":"crossref","DOI":"10.3390\/cancers14143305","article-title":"Targeted Therapeutic Options and Future Perspectives for HER2-Positive Breast Cancer","volume":"14","author":"Ferrando-D\u00edez","year":"2022","journal-title":"Cancers (Basel)"},{"key":"2026062607451784000_14.2.e012976.5","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/s41571-024-00924-9","article-title":"HER2-targeted therapies beyond breast cancer - 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