title: Mature B cells are critical to T-cell-mediated tumor immunity induced by an agonist anti-GITR monoclonal antibody.
abstract: An agonistic antibody DTA-1, to glucocorticoid-induced TNFR-related protein (GITR), induces T-cell activation and antitumor immunity. CD4(+) effector T cells are essential in initiating GITR-induced immune activation, and the sequentially activated cytolytic CD8(+) T cells are sufficient to induce tumor rejection. Administration of DTA-1 to a tumor-bearing mouse also induces B-cell activation illustrated by CD69 expression. Substantial evidence suggests that resting B cells are tumor promoting, which has prompted the idea of B-cell depletion by Rituximab, to be combined with other agents in the clinic to augment antitumor response. In this study, we have found that mature B cells are needed for the mechanism of anti-GITR agonist to kill tumors. The treatment of GITR agonist induces profound B-cell activation, differentiation, and antibody production. In a mature B-cell-deficient mouse (JHD), DTA-1 fails to induce tumor regression with a reduced early activation of CD4(+) and CD8(+) T cells. B-cell deficiency disables the capability of the DTA-1 in generating cytolytic CD8(+) T cells and significantly reduces the cytokine production in tumor bearing mice. The tumor-killing activities of DTA-1 are still present albeit reduced in the CD40(-/-) mice, in which IgG production is impaired. We have also shown that the dependence on B cells to kill tumors differentiates GITR costimulation from CTLA4 blockade and OX40 agonism in tumor immunotherapy. The findings underscore the reciprocal T-cell-B-cell interaction to enhance antitumor immunity upon GITR costimulation. The results provide the insight that attenuating B-cell functions may not be beneficial in cancer immunotherapy based on GITR agonism.
authors.affiliation: Discovery Research, Merck Research Laboratories--Palo Alto (Formerly DNAX Research Institute), Palo Alto, CA 94304, USA.
authors.forename: Pengfei
authors.initials: P
authors.lastname: Zhou
authors.forename: Junzhuan
authors.initials: J
authors.lastname: Qiu
authors.forename: Lawrence
authors.initials: L
authors.lastname: L'Italien
authors.forename: Danling
authors.initials: D
authors.lastname: Gu
authors.forename: Douglas
authors.initials: D
authors.lastname: Hodges
authors.forename: Cheng-Chi
authors.initials: CC
authors.lastname: Chao
authors.forename: Xiao Min
authors.initials: XM
authors.lastname: Schebye
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000494:pharmacology; D000917:Antibody Formation / Q000235:genetics; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D019013:CD40 Antigens / Q000235:genetics; D002450:Cell Communication; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007167:Immunotherapy; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D017475:Receptors, Nerve Growth Factor / Q000819:agonists / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000819:agonists / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse