Lymphoma depletion during CD20 immunotherapy in mice is mediated by macrophage FcgammaRI, FcgammaRIII, and FcgammaRIV.
Despite the demonstrated clinical efficacy of CD20 monoclonal antibody (mAb) for lymphoma therapy, the in vivo mechanisms of tumor depletion remain controversial and variable. To identify the molecular mechanisms responsible for lymphoma killing by CD20 mAb in a homologous system amenable to mechanistic studies and genetic manipulation, a mouse lymphoma model was developed using primary tumor cells from a C57BL/6 Emicro-cMyc transgenic mouse and mouse antimouse CD20 mAbs. CD20 mAb treatment of syngeneic mice with adoptively transferred lymphomas prevented tumor development or significantly prolonged mouse survival depending on tumor volume, mAb dose, and treatment timing. Cooperative FcgammaRIV, FcgammaRIII, and FcgammaRI interactions mediated optimal lymphoma depletion by CD20 mAb in vivo, whereas clodronate-mediated depletion of macrophages eliminated the therapeutic benefit of CD20 mAb. Although CD20 mAbs activated complement in vitro and in vivo, normal and malignant B-cell depletion was induced through C1q- and C3-independent mechanisms. Thus, the ability of CD20 mAbs to deplete malignant B cells in vivo required FcgammaR-dependent use of the innate mononuclear cell immune system. These findings allow for mechanism-based predictions of the biologic outcome of CD20 mAb therapy and treatment optimization.
Minard-Colin
Veronique
V
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Xiu
Yan
Y
Poe
Jonathan C
JC
Horikawa
Mayuka
M
Magro
Cynthia M
CM
Hamaguchi
Yasuhito
Y
Haas
Karen M
KM
Tedder
Thomas F
TF
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D018951:Antigens, CD20 / Q000276:immunology*; D004195:Disease Models, Animal; D007167:Immunotherapy / Q000379:methods*; D008212:Lymphocyte Depletion / Q000379:methods*; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D017452:Receptors, IgG / Q000276:immunology*; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D018951:Antigens, CD20; C485701:Fcgr1 protein, mouse; C485700:Fcgr3 protein, mouse; C522404:Fcgr4 protein, mouse; D017452:Receptors, IgG