{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:11:52Z","timestamp":1790741512985,"version":"4.1.0"},"reference-count":47,"publisher":"BMJ","issue":"7","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"unspecified","delay-in-days":2,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Boehringer Ingelheim","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,5,28]]},"published-print":{"date-parts":[[2026,7]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Fibroblast activating protein (FAP) expressing fibroblasts are an attractive target for cancer therapeutic depletion and while preclinical depletion shows success, previous modalities have had unsuccessful clinical impact. Here, we wanted to comprehensively understand the tumor microenvironmental changes after FAP\n                      <jats:sup>+<\/jats:sup>\n                      fibroblast depletion and unravel potential reasons for resistance and vulnerabilities that appear upon treatment with a FAP-targeted T-cell engager. To unveil the complex changes that occur in the tumor microenvironment (TME) after FAP\n                      <jats:sup>+<\/jats:sup>\n                      fibroblast depletion, we generated comprehensive single-cell RNA-sequencing analysis of FAP\n                      <jats:sup>+<\/jats:sup>\n                      cancer-associated fibroblasts (CAFs) depletion within the TME to understand the key populations and genetic modulations in all cell subtypes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A CD3 T-cell engager directed against FAP (FAP TcE) was used to deplete FAP\n                      <jats:sup>+<\/jats:sup>\n                      fibroblasts in a preclinical murine model of pancreatic cancer. To understand complex population dynamics on FAP TcE, we performed single-cell RNA-sequencing of treated versus untreated tumors to unveil population and genetic changes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Administration of FAP TcE resulted in tumor growth control in vivo that was not dependent on T-cell priming and egress via draining lymph nodes. After FAP TcE, T-cell exhaustion was prevalent with an increased T-cell exhaustive state and the emergence of a T-cell progenitor exhausted state, yet the addition of anti-programmed cell death protein 1 (PD-1) failed to enhance tumor efficacy. Within fibroblast populations, FAP TcE depleted FAP\n                      <jats:sup>+<\/jats:sup>\n                      CAFs; however, depletion is compensated by an emergence of a \u201cmixed CAF\u201d population, potentially limiting the efficacy of FAP TcE.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study highlights the complex and plastic fibroblast changes occurring with stroma-targeted therapies that may limit therapeutic efficacy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-014551","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:15:31Z","timestamp":1783084531000},"page":"e014551","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":2,"title":["Emergence of a mixed CAF population by FAP-CD3 T-cell engager limits therapeutic efficacy"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4245-6770","authenticated-orcid":false,"given":"Robert J","family":"Norgard","sequence":"first","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-3591-6441","authenticated-orcid":false,"given":"Joshua R","family":"Tagore","sequence":"additional","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pratha","family":"Budhani","sequence":"additional","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sai Charan","family":"Penikalapati","sequence":"additional","affiliation":[{"name":"Computational Innovation, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priyanka","family":"Gupta","sequence":"additional","affiliation":[{"name":"Biotherapeutics, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongmei","family":"Liu","sequence":"additional","affiliation":[{"name":"Biotherapeutics, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica N","family":"Egan","sequence":"additional","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah F","family":"Finnegan","sequence":"additional","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuxuan","family":"Li","sequence":"additional","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brianna","family":"Flynn","sequence":"additional","affiliation":[{"name":"Nonclinical Safety, Boehringer Ingelheim Pharmaceutical Inc, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Reichel-Voda","sequence":"additional","affiliation":[{"name":"Oncology Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leticia","family":"Corrales","sequence":"additional","affiliation":[{"name":"Oncology Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bachmayr-Heyda","sequence":"additional","affiliation":[{"name":"Oncology Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I\u00f1igo","family":"Tirapu","sequence":"additional","affiliation":[{"name":"Oncology Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abhishek S","family":"Kashyap","sequence":"additional","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youli","family":"Xia","sequence":"additional","affiliation":[{"name":"Computational Innovation, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah A","family":"O\u2019Brien","sequence":"additional","affiliation":[{"name":"Oncology, Boehringer Ingelheim Corp USA, Ridgefield, Connecticut, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,7,3]]},"reference":[{"key":"2026070306151080000_14.7.e014551.1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.57243","article-title":"Cancer-associated fibroblasts and their influence on tumor immunity and immunotherapy","volume":"9","author":"Barrett","year":"2020","journal-title":"Elife"},{"key":"2026070306151080000_14.7.e014551.2","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-009702","article-title":"Cancer-associated fibroblast targeting therapies as a tool to enhance responses to radiotherapy and immunotherapy","volume":"14","author":"Garate-Soraluze","year":"2026","journal-title":"J Immunother Cancer"},{"key":"2026070306151080000_14.7.e014551.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.04.005"},{"key":"2026070306151080000_14.7.e014551.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.04.021"},{"key":"2026070306151080000_14.7.e014551.5","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1111\/cas.16443","article-title":"Targeting Cancer-Associated Fibroblasts: Eliminate or Reprogram?","volume":"116","author":"Yamazaki","year":"2025","journal-title":"Cancer Sci"},{"key":"2026070306151080000_14.7.e014551.6","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0094"},{"key":"2026070306151080000_14.7.e014551.7","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20162024"},{"key":"2026070306151080000_14.7.e014551.8","doi-asserted-by":"crossref","DOI":"10.1186\/s12943-024-02191-9","article-title":"Single cell and spatial analysis of immune-hot and immune-cold tumours identifies fibroblast subtypes associated with distinct immunological niches and positive immunotherapy response","volume":"24","author":"Jenkins","year":"2025","journal-title":"Mol Cancer"},{"key":"2026070306151080000_14.7.e014551.9","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1016\/j.trecan.2019.09.010","article-title":"CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer","volume":"5","author":"Pereira","year":"2019","journal-title":"Trends Cancer"},{"key":"2026070306151080000_14.7.e014551.10","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2020.101417"},{"key":"2026070306151080000_14.7.e014551.11","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.semcancer.2021.03.006","article-title":"Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment","volume":"82","author":"Boyd","year":"2022","journal-title":"Semin Cancer Biol"},{"key":"2026070306151080000_14.7.e014551.12","doi-asserted-by":"crossref","DOI":"10.3389\/fonc.2021.648187","article-title":"Fibroblast Activation Protein-\u03b1 as a Target in the Bench-to-Bedside Diagnosis and Treatment of Tumors: A Narrative Review","volume":"11","author":"Xin","year":"2021","journal-title":"Front Oncol"},{"key":"2026070306151080000_14.7.e014551.13","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2973"},{"key":"2026070306151080000_14.7.e014551.14","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1320318110"},{"key":"2026070306151080000_14.7.e014551.15","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-18-1750"},{"key":"2026070306151080000_14.7.e014551.16","doi-asserted-by":"publisher","DOI":"10.1097\/CJI.0b013e3182594387"},{"key":"2026070306151080000_14.7.e014551.17","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-13-0027"},{"key":"2026070306151080000_14.7.e014551.18","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-3041"},{"key":"2026070306151080000_14.7.e014551.19","doi-asserted-by":"crossref","DOI":"10.1186\/s40425-019-0505-4","article-title":"Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager","volume":"7","author":"de Sostoa","year":"2019","journal-title":"J Immunother Cancer"},{"key":"2026070306151080000_14.7.e014551.20","doi-asserted-by":"publisher","DOI":"10.1038\/mt.2013.110"},{"key":"2026070306151080000_14.7.e014551.21","doi-asserted-by":"crossref","first-page":"1481","DOI":"10.1158\/2767-9764.CRC-24-0248","article-title":"Mechanistic Characterization of Cancer-associated Fibroblast Depletion via an Antibody-Drug Conjugate Targeting Fibroblast Activation Protein","volume":"4","author":"Gallant","year":"2024","journal-title":"Cancer Res Commun"},{"key":"2026070306151080000_14.7.e014551.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2018.06.006"},{"key":"2026070306151080000_14.7.e014551.23","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.92232","article-title":"Fibroblast activation protein augments progression and metastasis of pancreatic ductal adenocarcinoma","volume":"2","author":"Lo","year":"2017","journal-title":"JCI Insight"},{"key":"2026070306151080000_14.7.e014551.24","doi-asserted-by":"crossref","DOI":"10.1126\/scitranslmed.abd1524","article-title":"Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell-cold solid tumors","volume":"13","author":"Belmontes","year":"2021","journal-title":"Sci Transl Med"},{"key":"2026070306151080000_14.7.e014551.25","doi-asserted-by":"crossref","DOI":"10.1172\/JCI166070","article-title":"Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma","volume":"133","author":"Apollonio","year":"2023","journal-title":"J Clin Invest"},{"key":"2026070306151080000_14.7.e014551.26","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-07-5211"},{"key":"2026070306151080000_14.7.e014551.27","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.332783"},{"key":"2026070306151080000_14.7.e014551.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.08.064"},{"key":"2026070306151080000_14.7.e014551.29","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-0926"},{"key":"2026070306151080000_14.7.e014551.30","doi-asserted-by":"publisher","DOI":"10.1111\/imr.13379"},{"key":"2026070306151080000_14.7.e014551.31","doi-asserted-by":"crossref","DOI":"10.1002\/biot.202000251","article-title":"Optimization of a transient antibody expression platform towards high titer and efficiency","volume":"16","author":"Greene","year":"2021","journal-title":"Biotechnol J"},{"key":"2026070306151080000_14.7.e014551.32","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2022.1008764","article-title":"LY6G6D is a selectively expressed colorectal cancer antigen that can be used for targeting a therapeutic T-cell response by a T-cell engager","volume":"13","author":"Corrales","year":"2022","journal-title":"Front Immunol"},{"key":"2026070306151080000_14.7.e014551.33","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1412910111"},{"key":"2026070306151080000_14.7.e014551.34","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-2320"},{"key":"2026070306151080000_14.7.e014551.35","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1038\/s41586-022-05272-1","article-title":"LRRC15+ myofibroblasts dictate the stromal setpoint to suppress tumour immunity","volume":"611","author":"Krishnamurty","year":"2022","journal-title":"Nature New Biol"},{"key":"2026070306151080000_14.7.e014551.36","doi-asserted-by":"crossref","first-page":"2388","DOI":"10.1158\/0008-5472.CAN-23-3252","article-title":"Dissecting FAP+ Cell Diversity in Pancreatic Cancer Uncovers an Interferon-Response Subtype of Cancer-Associated Fibroblasts with Tumor-Restraining Properties","volume":"85","author":"Cumming","year":"2025","journal-title":"Cancer Res"},{"key":"2026070306151080000_14.7.e014551.37","doi-asserted-by":"crossref","DOI":"10.1016\/j.esmoop.2020.100046","article-title":"Immune cell engagers in solid tumors: promises and challenges of the next generation immunotherapy","volume":"6","author":"Fuc\u00e0","year":"2021","journal-title":"ESMO Open"},{"key":"2026070306151080000_14.7.e014551.38","doi-asserted-by":"crossref","DOI":"10.1172\/jci.insight.88328","article-title":"Lack of immunoediting in murine pancreatic cancer reversed with neoantigen","volume":"1","author":"Evans","year":"2016","journal-title":"JCI Insight"},{"key":"2026070306151080000_14.7.e014551.39","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nature19330","article-title":"Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy","volume":"537","author":"Im","year":"2016","journal-title":"Nature New Biol"},{"key":"2026070306151080000_14.7.e014551.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0312-6"},{"key":"2026070306151080000_14.7.e014551.41","doi-asserted-by":"crossref","DOI":"10.1038\/s41392-023-01595-1","article-title":"From Tpex to Tex: a journey through CD8+ T cell responses in cancer immunotherapy","volume":"8","author":"Messmer","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"2026070306151080000_14.7.e014551.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0441-y"},{"key":"2026070306151080000_14.7.e014551.43","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2024-011145","article-title":"PD-1 blockade employed at the time CD8+ T cells are activated enhances their antitumor efficacy","volume":"13","author":"Moseman","year":"2025","journal-title":"J Immunother Cancer"},{"key":"2026070306151080000_14.7.e014551.44","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0644"},{"key":"2026070306151080000_14.7.e014551.45","doi-asserted-by":"crossref","DOI":"10.1073\/pnas.2020395118","article-title":"IL17A critically shapes the transcriptional program of fibroblasts in pancreatic cancer and switches on their protumorigenic functions","volume":"118","author":"Mucciolo","year":"2021","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026070306151080000_14.7.e014551.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0367-4"},{"key":"2026070306151080000_14.7.e014551.47","doi-asserted-by":"crossref","first-page":"1548","DOI":"10.1158\/2767-9764.CRC-24-0172","article-title":"Reshaping the Tumor Microenvironment of KRASG12D Pancreatic Ductal Adenocarcinoma with Combined SOS1 and MEK Inhibition for Improved Immunotherapy Response","volume":"4","author":"Norgard","year":"2024","journal-title":"Cancer Res Commun"}],"container-title":["Journal for ImmunoTherapy of Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jitc-2025-014551","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T13:15:35Z","timestamp":1783084535000},"score":1,"resource":{"primary":{"URL":"https:\/\/jitc.bmj.com\/lookup\/doi\/10.1136\/jitc-2025-014551"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7]]},"references-count":47,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7,3]]},"published-print":{"date-parts":[[2026,7]]}},"alternative-id":["10.1136\/jitc-2025-014551"],"URL":"https:\/\/doi.org\/10.1136\/jitc-2025-014551","relation":{},"ISSN":["2051-1426"],"issn-type":[{"value":"2051-1426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7]]}}}