CD137 ligand is expressed in primary and secondary lymphoid follicles and in B-cell lymphomas: diagnostic and therapeutic implications.

CD137 ligand (4-1BB ligand, TNFSF9, CD137L) is a member of the tumor necrosis factor family whose binding to its receptor, CD137 (4-1BB, TNFRSF9), mediates costimulatory and prosurvival signals necessary for T-cell activation and regulation of humoral immune responses. Recent studies have shown that anti-CD137 immunotherapy has promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. Here, we define the tissue expression profile of CD137L, which has not been previously explored. We characterized the expression of CD137L in normal and neoplastic human hematopoietic and nonhematopoietic tissue and found that CD137L is preferentially expressed in B cells of the primary follicles, mantle zones of the secondary follicles, germinal centers, and in normal endothelial cells. Double immunofluorescence labeling in tissue sections and flow cytometry analysis further showed that CD137L is a potential new marker of memory B cells. Evaluation of over 700 human hematopoietic tumors revealed that the majority of B-cell lymphomas expressed CD137L, which include mantle cell lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. In contrast, CD137L expression was lacking in Hodgkin lymphoma and T-cell lymphoma. Our findings suggest that CD137L is a novel diagnostic marker of subtypes of non-Hodgkin B-cell lymphomas and raise the possibility that its expression on tumor cells may be directly targeted for immunomodulatory therapy for lymphoid and other malignancies.