In vitro mechanisms of action of rituximab on primary non-Hodgkin lymphomas.
To assess the sensitivity of primary non-Hodgkin lymphoma cells to rituximab-mediated cytotoxicity, we compared the potency of several rituximab-mediated killing mechanisms on fresh lymphoma cells. All lymphoma cells tested were equally sensitive to antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-mediated phagocytosis of tumor cells, and rituximab-induced apoptosis. However, they were differentially lysed by complement-dependent cytotoxicity (CDC). We found that taking into account both CD20 and complement regulatory protein expression on tumor cells could predict CDC sensitivity in vitro. Importantly, the sensitivity of lymphoma cells to CDC was consistent with the reported different clinical response rates of lymphomas: rituximab induced high CDC killing of follicular lymphoma cells, whereas mantle cell lymphoma and diffuse large cell lymphoma cells were moderately sensible to CDC, and small lymphocytic lymphoma cells were almost all resistant. We propose that CDC is a determinant mechanism of rituximab-induced killing in vivo. Poor sensitivity to CDC in vitro might predict a poor clinical response, whereas high sensitivity to CDC would only indicate a likelihood of response to rituximab treatment.
Manches
Olivier
O
Department of Research and Development, EFS Rhône-Alpes, and Research Group on Lymphoma, Albert Bonniot Institute, La Tronche, France.
Lui
Gabrielle
G
Chaperot
Laurence
L
Gressin
Rémy
R
Molens
Jean-Paul
JP
Jacob
Marie-Christine
MC
Sotto
Jean-Jacques
JJ
Leroux
Dominique
D
Bensa
Jean-Claude
JC
Plumas
Joël
J
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20 / Q000032:analysis / Q000276:immunology; D000951:Antigens, Neoplasm / Q000032:analysis / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D016923:Cell Death / Q000187:drug effects; D003165:Complement System Proteins; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006801:Humans; D008198:Lymph Nodes / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000473:pathology; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000473:pathology*; D010587:Phagocytosis / Q000187:drug effects; D000069283:Rituximab
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D000069283:Rituximab; D003165:Complement System Proteins