{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T20:54:12Z","timestamp":1793652852524,"version":"4.5.1"},"reference-count":56,"publisher":"American Society of Hematology","issue":"17","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,9,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Classic Hodgkin lymphoma (cHL) responds markedly to PD-1 blockade therapy, and the clinical responses are reportedly dependent on expression of major histocompatibility complex class II (MHC-II). This dependence is different from other solid tumors, in which the MHC class I (MHC-I)\/CD8+ T-cell axis plays a critical role. In this study, we investigated the role of the MHC-II\/CD4+ T-cell axis in the antitumor effect of PD-1 blockade on cHL. In cHL, MHC-I expression was frequently lost, but MHC-II expression was maintained. CD4+ T cells highly infiltrated the tumor microenvironment of MHC-II\u2013expressing cHL, regardless of MHC-I expression status. Consequently, CD4+ T-cell, but not CD8+ T-cell, infiltration was a good prognostic factor in cHL, and PD-1 blockade showed antitumor efficacy against MHC-II\u2013expressing cHL associated with CD4+ T-cell infiltration. Murine lymphoma and solid tumor models revealed the critical role of antitumor effects mediated by CD4+ T cells: an anti-PD-1 monoclonal antibody exerted antitumor effects on MHC-I\u2212MHC-II+ tumors but not on MHC-I\u2212MHC-II\u2212 tumors, in a cytotoxic CD4+ T-cell\u2013dependent manner. Furthermore, LAG-3, which reportedly binds to MHC-II, was highly expressed by tumor-infiltrating CD4+ T cells in MHC-II\u2013expressing tumors. Therefore, the combination of LAG-3 blockade with PD-1 blockade showed a far stronger antitumor immunity compared with either treatment alone. We propose that PD-1 blockade therapies have antitumor effects on MHC-II\u2013expressing tumors such as cHL that are mediated by cytotoxic CD4+ T cells and that LAG-3 could be a candidate for combination therapy with PD-1 blockade.<\/jats:p>","DOI":"10.1182\/bloodadvances.2020002098","type":"journal-article","created":{"date-parts":[[2020,9,1]],"date-time":"2020-09-01T14:45:58Z","timestamp":1598971558000},"page":"4069-4082","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":128,"title":["The critical role of CD4+ T cells in PD-1 blockade against MHC-II\u2013expressing tumors such as classic Hodgkin lymphoma"],"prefix":"10.1182","volume":"4","author":[{"given":"Joji","family":"Nagasaki","sequence":"first","affiliation":[{"name":"Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan;"},{"name":"Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, 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Pathology, Chiba Cancer Center, Chiba, Japan;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nobuhiko","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan;"},{"name":"Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, Japan;"},{"name":"Depertment of Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junichiro","family":"Yuda","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan;"},{"name":"Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, Japan;"},{"name":"Depertment of Hematology and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2695-8172","authenticated-orcid":false,"given":"Masato","family":"Sugano","sequence":"additional","affiliation":[{"name":"Department of Pathology, National Cancer Center Hospital East, Kashiwa, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuuki","family":"Ohara","sequence":"additional","affiliation":[{"name":"Division of Cancer Immunology, Research Institute, National Cancer Center, Tokyo, Japan;"},{"name":"Exploratory Oncology Research and Clinical Trial Center (EPOC), National Cancer Center, Kashiwa, Japan;"},{"name":"Department of Pathology, National Cancer Center Hospital East, Kashiwa, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Minami","sequence":"additional","affiliation":[{"name":"Depertment of Hematology 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