{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:25:31Z","timestamp":1788881131119,"version":"build-2803163510"},"reference-count":24,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Follicular helper T-cell (TFH)-type lymphomas, including angioimmunoblastic T-cell lymphoma (AITL) and TFH lymphoma, not otherwise specified (TFH-NOS), are characterized by marked immune dysregulation in the tumor microenvironment. We investigated whether TFH-type lymphomas are enriched in immunosuppressive cells and explored immunologic changes associated with denileukin diftitox (DD) treatment. Methods: FOXP3-positive mononuclear cells were quantified by immunohistochemistry in lymph node specimens from 10 patients with TFH-type lymphoma and six with non-TFH-type T-cell lymphoma. Paired skin biopsy specimens obtained before and after DD treatment from two patients with AITL were evaluated for CD4, CD8, CD68, CD163, and FOXP3 expression. Longitudinal flow cytometric T-cell receptor V\u03b2 repertoire analysis of CD8-positive T-cell subsets was performed in three patients with AITL treated with DD. Clinical responses were retrospectively assessed in seven patients with relapsed or refractory TFH-type lymphoma treated with DD. Results: TFH-type lymphomas showed significantly higher intra-tumoral FOXP3-positive cell densities than non-TFH-type lymphomas (p = 0.0024). In paired skin biopsies, DD treatment was associated with reductions in CD68- and CD163-positive macrophage-rich infiltrates and a suggested decrease in FOXP3-positive cells. Among seven patients treated with DD, the overall response rate was 86%, including one complete response and five partial responses. Responders showed selective V\u03b2 over-representation patterns in effector and\/or memory CD8-positive T-cell subsets, whereas such findings were not convincing in the non-responder. Conclusions: TFH-type lymphomas were associated with higher FOXP3-positive cell density than selected non-TFH-type comparators. DD treatment may be associated with changes in tissue immune infiltrates and peripheral CD8\/TCR V\u03b2 skewing in responding cases, although these findings remain exploratory and do not establish causality.<\/jats:p>","DOI":"10.3390\/cancers18101529","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T12:05:22Z","timestamp":1778501122000},"page":"1529","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Immune Correlates of Denileukin Diftitox Treatment in TFH-Type Lymphoma"],"prefix":"10.3390","volume":"18","author":[{"given":"Tatsuro","family":"Jo","sequence":"first","affiliation":[{"name":"Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Sakai","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaori","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaho","family":"Umemoto","sequence":"additional","affiliation":[{"name":"Department of Clinical Laboratory, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masatoshi","family":"Matsuo","sequence":"additional","affiliation":[{"name":"Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Sawayama","sequence":"additional","affiliation":[{"name":"Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Taguchi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0623-038X","authenticated-orcid":false,"given":"Ritsuko","family":"Kubota-Koketsu","sequence":"additional","affiliation":[{"name":"Specimen Analysis Team, Human Resource Development Division, Center for Infectious Disease Education and Research, The University of Osaka, Yamadaoka 2-2, Suita City 565-0871, Osaka, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kuniko","family":"Abe","sequence":"additional","affiliation":[{"name":"Department of Pathology, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuto","family":"Shigematsu","sequence":"additional","affiliation":[{"name":"Department of Pathology, Japanese Red Cross Nagasaki Genbaku Hospital, Mori-machi 3-15, Nagasaki City 852-8511, Nagasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1720","DOI":"10.1038\/s41375-022-01620-2","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms","volume":"36","author":"Alaggio","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1182\/blood.2022015851","article-title":"The International Consensus Classification of Mature Lymphoid Neoplasms: A report from the Clinical Advisory Committee","volume":"140","author":"Campo","year":"2022","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1046\/j.1365-2141.2003.04335.x","article-title":"Angioimmunoblastic T-cell lymphoma","volume":"121","author":"Dogan","year":"2003","journal-title":"Br. 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