title: Robust Antitumor Effects of Combined Anti-CD4-Depleting Antibody and Anti-PD-1/PD-L1 Immune Checkpoint Antibody Treatment in Mice.
abstract: Depletion of CD4(+) cells in tumor-bearing mice has strong antitumor effects. However, the mechanisms underlying these effects and the therapeutic benefits of CD4(+) cell depletion relative to other immunotherapies have not been fully evaluated. Here, we investigated the antitumor effects of an anti-CD4-depleting mAb as a monotherapy or in combination with immune checkpoint mAbs. In B16F10, Colon 26, or Lewis lung carcinoma subcutaneous tumor models, administration of the anti-CD4 mAb alone had strong antitumor effects that were superior to those elicited by CD25(+) Treg depletion or other immune checkpoint mAbs, and which were completely reversed by CD8(+) cell depletion. CD4(+) cell depletion led to the proliferation of tumor-specific CD8(+) T cells in the draining lymph node and increased infiltration of PD-1(+)CD8(+) T cells into the tumor, with a shift toward type I immunity within the tumor. Combination treatment with the anti-CD4 mAb and immune checkpoint mAbs, particularly anti-PD-1 or anti-PD-L1 mAbs, synergistically suppressed tumor growth and greatly prolonged survival. To our knowledge, this work represents the first report of robust synergy between anti-CD4 and anti-PD-1 or anti-PD-L1 mAb therapies.
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IDAC Theranostics, Inc., Tokyo, Japan.
authors.forename: Shoji
authors.initials: S
authors.lastname: Yokochi
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IDAC Theranostics, Inc., Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Ishiwata
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Haru
authors.initials: H
authors.lastname: Ogiwara
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Krishant
authors.initials: K
authors.lastname: Chand
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Nakajima
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IDAC Theranostics, Inc., Tokyo, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Hachiga
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Shichino
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Yuya
authors.initials: Y
authors.lastname: Terashima
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Etsuko
authors.initials: E
authors.lastname: Toda
authors.affiliation: Department of Pharmacology and Therapeutics, The University of Melbourne, Melbourne, Victoria, Australia.
authors.forename: Francis H W
authors.initials: FH
authors.lastname: Shand
authors.affiliation: Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kakimi
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. IDAC Theranostics, Inc., Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Ito
authors.affiliation: Department of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. koujim@m.u-tokyo.ac.jp.
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors*; D015704:CD4 Antigens; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006801:Humans; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008212:Lymphocyte Depletion; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism; D008297:Male; D008546:Melanoma, Experimental; D051379:Mice; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D015704:CD4 Antigens; D061026:Programmed Cell Death 1 Receptor