{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T03:25:33Z","timestamp":1793330733670,"version":"4.5.0"},"reference-count":82,"publisher":"American Society of Hematology","issue":"18","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2026,10,29]]},"abstract":"<jats:sec>\n                    <jats:title>Abstract<\/jats:title>\n                    <jats:p>Immunotherapy has revolutionized the treatment of solid cancers in recent years. However, T-cell non-Hodgkin lymphomas (T-NHL) originate from immune cells themselves and are biologically heterogeneous, rendering investigations of immune checkpoint inhibitor (ICI) mechanisms of action complex. Although case reports and individual anaplastic large cell lymphoma (ALCL) patients enrolled in T-NHL trials demonstrated favorable responses to ICIs, hyperprogression was observed in other T-NHL subtypes. We therefore used a syngeneic mouse model of anaplastic lymphoma kinase positive (ALK+) ALCL to investigate immune surveillance and ICI-induced immune response. Transplantation experiments combined with the depletion of relevant immune axes revealed that ALCL immune surveillance is mediated by CD4+ T cells and natural killer cells. Innate and adaptive immune cell infiltration was confirmed in a large series of primary human ALK+ ALCL samples. ICI monotherapy demonstrated robust efficacy in murine ALCL, inducing complete remissions in \u223c50% of treated animals. Mechanistically, PD-L1 blockade reversed regulatory T cell-mediated immunosuppression and increased the frequency of circulating effector CD8+ T lymphocytes, thereby significantly prolonging survival. Importantly, CD4+ T cells proved indispensable for driving and sustaining immunotherapy-induced antitumor responses in murine ALCL. CD4+ T cells of nonresponder animals exhibited an exhausted phenotype and a transcriptomic T helper 22\u2013like signature, implicating persistent T-cell exhaustion and polarization as a meaningful immune evasion mechanism. Our findings uncover CD4+ T cells as key players in spontaneous and immunotherapy-mediated anti\u2013T-cell lymphoma immunity, which demonstrates the critically needed preclinical proof-of-concept for the safe and effective use of immunotherapy for ALCL.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1182\/blood.2026033240","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T18:58:51Z","timestamp":1785265131000},"page":"2264-2277","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["CD4+ T cells orchestrate the immune response to ALK-positive T-cell lymphoma"],"prefix":"10.1182","volume":"148","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2560-8488","authenticated-orcid":false,"given":"Teresa","family":"Poggio","sequence":"first","affiliation":[{"name":"1Department of Internal Medicine I, Haematology, Oncology and Stem Cell Transplantation, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"2Faculty of Biology, University of Freiburg, Freiburg, Germany"},{"name":"3German Cancer Consortium (DKTK), Partner site Freiburg \u2013 a partnership between German Cancer Research Center (DKFZ) and Medical Center \u2013 University of Freiburg, Freiburg, Germany"},{"name":"4European Research Initiative for ALK-related malignancies"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-2988-9766","authenticated-orcid":false,"given":"Linda","family":"Gr\u00e4\u00dfel","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Haematology, Oncology and Stem Cell Transplantation, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"3German Cancer Consortium (DKTK), Partner site Freiburg \u2013 a partnership between German Cancer Research Center (DKFZ) and Medical Center \u2013 University of Freiburg, Freiburg, Germany"},{"name":"5Clinic for Hematology and Medical Oncology, University Medical Center G\u00f6ttingen, Georg-August-University G\u00f6ttingen, G\u00f6ttingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5389-9481","authenticated-orcid":false,"given":"Geoffroy","family":"Andrieux","sequence":"additional","affiliation":[{"name":"6Institute of Medical Bioinformatics and Systems Medicine, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana M.","family":"G\u00f3mez Mart\u00ednez","sequence":"additional","affiliation":[{"name":"5Clinic for Hematology and Medical Oncology, University Medical Center G\u00f6ttingen, Georg-August-University G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"7Center for Personalized Medicine, TUM Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany"},{"name":"8Clinic and Polyclinic for Haematology and Oncology, Faculty of Medicine, Technical University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Stock","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Haematology, Oncology and Stem Cell Transplantation, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"2Faculty of Biology, University of Freiburg, Freiburg, Germany"},{"name":"3German Cancer Consortium (DKTK), Partner site Freiburg \u2013 a partnership between German Cancer Research Center (DKFZ) and Medical Center \u2013 University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3251-0432","authenticated-orcid":false,"given":"Magdalena","family":"Kr\u0161i\u0107","sequence":"additional","affiliation":[{"name":"7Center for Personalized Medicine, TUM Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany"},{"name":"8Clinic and Polyclinic for Haematology and Oncology, Faculty of Medicine, Technical University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Gonzalez-Menendez","sequence":"additional","affiliation":[{"name":"9Institute of Pathology and Neuropathology, Comprehensive Cancer Center, University Hospital T\u00fcbingen, T\u00fcbingen, Germany"},{"name":"10Core Facility Histology, Faculty of Medicine T\u00fcbingen, University Hospital T\u00fcbingen, T\u00fcbingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8466-6675","authenticated-orcid":false,"given":"Stefanie","family":"Kreutmair","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Haematology, Oncology and Stem Cell Transplantation, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"3German Cancer Consortium (DKTK), Partner site Freiburg \u2013 a partnership between German Cancer Research Center (DKFZ) and Medical Center \u2013 University of Freiburg, Freiburg, Germany"},{"name":"11Department of Medical Oncology and Haematology, University Hospital Zurich, Zurich, Switzerland"},{"name":"12Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland"},{"name":"13The LOOP Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-8628-7207","authenticated-orcid":false,"given":"Catarina","family":"Reis Orcinha","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Haematology, Oncology and Stem Cell Transplantation, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"3German Cancer Consortium (DKTK), Partner site Freiburg \u2013 a partnership between German Cancer Research Center (DKFZ) and Medical Center \u2013 University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marissa","family":"Russ","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Haematology, Oncology and Stem Cell Transplantation, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany"},{"name":"2Faculty of Biology, University of Freiburg, Freiburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salome","family":"Yacob","sequence":"additional","affiliation":[{"name":"5Clinic for Hematology and Medical Oncology, University Medical Center G\u00f6ttingen, Georg-August-University G\u00f6ttingen, G\u00f6ttingen, Germany"},{"name":"7Center for Personalized Medicine, TUM Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany"},{"name":"8Clinic and Polyclinic for Haematology and Oncology, Faculty of Medicine, Technical University of Munich, Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4699-3805","authenticated-orcid":false,"given":"Cornelius","family":"Miething","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine I, Haematology, Oncology and Stem Cell Transplantation, Medical Center \u2013 University of Freiburg, Faculty of Medicine, University of Freiburg, 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