title: CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma.
abstract: The primary function of B cells, critical components of the adaptive immune response, is to produce antibodies against foreign antigens, as well as to perform isotype class switching, which changes the heavy chain of an antibody so that it can interact with different repertoires of effector cells. CD40 is a member of the tumor necrosis factor superfamily of cell surface receptors that transmits survival signals to B cells. In contrast, in B cell cancers, stimulation of CD40 signaling results in a heterogeneous response in which cells can sometimes undergo cell death in response to treatment, depending on the system studied. We found an association between sensitivity to CD40 stimulation and mutation of the tumor suppressor p53 in a panel of non-Hodgkin's lymphoma cell lines. Consistent with p53's tumor suppressor role, we found that higher levels of intrinsic DNA damage and increased proliferation rates, as well as higher levels of BCL6, a transcriptional repressor proto-oncogene, were associated with sensitivity to CD40 stimulation. In addition, CD40 treatment-resistant cell lines were sensitized to CD40 stimulation after the introduction of DNA-damaging agents. Using gene expression analysis, we also showed that resistant cell lines exhibited a preexisting activated CD40 pathway and that an mRNA expression signature comprising CD40 target genes predicted sensitivity and resistance to CD40-activating agents in cell lines and mouse xenograft models. Finally, the gene signature predicted tumor shrinkage and progression-free survival in patients with diffuse large B cell lymphoma treated with dacetuzumab, a monoclonal antibody with partial CD40 agonist activity. These data show that CD40 pathway activation status may be useful in predicting the antitumor activity of CD40-stimulating therapeutic drugs.
authors.affiliation: Department of Biostatistics, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Bart
authors.initials: B
authors.lastname: Burington
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Shi
authors.forename: Ranjana
authors.initials: R
authors.lastname: Advani
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Lau
authors.forename: Jenille
authors.initials: J
authors.lastname: Tan
authors.forename: Susanna
authors.initials: S
authors.lastname: Stinson
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Thomas
authors.initials: T
authors.lastname: Januario
authors.forename: Sven
authors.initials: S
authors.lastname: de Vos
authors.forename: Stephen
authors.initials: S
authors.lastname: Ansell
authors.forename: Andres
authors.initials: A
authors.lastname: Forero-Torres
authors.forename: Grazyna
authors.initials: G
authors.lastname: Fedorowicz
authors.forename: Teddy T C
authors.initials: TT
authors.lastname: Yang
authors.forename: Kristi
authors.initials: K
authors.lastname: Elkins
authors.forename: Changchun
authors.initials: C
authors.lastname: Du
authors.forename: Sankar
authors.initials: S
authors.lastname: Mohan
authors.forename: Nancy
authors.initials: N
authors.lastname: Yu
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Shang-Fan
authors.initials: SF
authors.lastname: Yu
authors.forename: Ajay
authors.initials: A
authors.lastname: Pandita
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.forename: Dorothy
authors.initials: D
authors.lastname: French
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Polson
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Nancy
authors.initials: N
authors.lastname: Whiting
authors.forename: Allen
authors.initials: A
authors.lastname: Ebens
authors.forename: David
authors.initials: D
authors.lastname: Dornan
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology*; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D017404:In Situ Hybridization, Fluorescence; D016403:Lymphoma, Large B-Cell, Diffuse / Q000188:drug therapy* / Q000276:immunology*; D051379:Mice; D046228:Microarray Analysis; D000090063:Proto-Oncogene Mas; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019013:CD40 Antigens; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D016159:Tumor Suppressor Protein p53; D023201:CD40 Ligand; C543331:dacetuzumab