TY - JOUR
T1 - CD40 pathway activation status predicts response to CD40 therapy in diffuse large B cell lymphoma
AU - Burington, Bart
AU - Yue, Peng
AU - Shi, Xiaoyan
AU - Advani, Ranjana
AU - Lau, Jeffrey T.
AU - Tan, Jenille
AU - Stinson, Susanna
AU - Stinson, Jeremy
AU - Januario, Thomas
AU - De Vos, Sven
AU - Ansell, Stephen
AU - Forero-Torres, Andres
AU - Fedorowicz, Grazyna
AU - Yang, Teddy T.C.
AU - Elkins, Kristi
AU - Du, Changchun
AU - Mohan, Sankar
AU - Yu, Nancy
AU - Modrusan, Zora
AU - Seshagiri, Somasekar
AU - Yu, Shang Fan
AU - Pandita, Ajay
AU - Koeppen, Hartmut
AU - French, Dorothy
AU - Polson, Andrew G.
AU - Offringa, Rienk
AU - Whiting, Nancy
AU - Ebens, Allen
AU - Dornan, David
PY - 2011/3/16
Y1 - 2011/3/16
N2 - 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.
AB - 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.
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U2 - 10.1126/scitranslmed.3001620
DO - 10.1126/scitranslmed.3001620
M3 - Article
C2 - 21411738
AN - SCOPUS:79952808845
SN - 1946-6234
VL - 3
JO - Science translational medicine
JF - Science translational medicine
IS - 74
M1 - 74ra22
ER -