Expression of CD137 Protein in Select Hematopoietic Tumors: Implications for Anti-CD137 Immunomodulatory Therapy.
Matthew W Anderson, Aharon G Freud, Shuchun Zhao, Arash A Alizadeh, Holbrook E Kohrt, Roger Warnke, Ronald Levy, Yasodha Natkunam. Stanford, Stanford, CA
Background: CD137 (4-1BB), a tumor necrosis factor family member, is a co-stimulatory molecule expressed on a variety of hematopoietic cells, including T, NK and follicular dendritic cells (FDC). We previously constructed a two-gene model showing that the expression of CD137 and the germinal center (GC) marker LMO2, powerfully predicts outcome in patients with diffuse large B-cell lymphoma. Anti-CD137 agonistic antibodies have shown therapeutic efficacy in human solid-organ malignancies and mouse models of lymphoma and myeloma. We characterized the expression pattern of the CD137 protein to better understand its role in normal immune response and lymphomagenesis.
Design: An anti-CD137 antibody (clone BBK-2, Thermo Scientific, Fremont, CA) was optimized for use on paraffin tissue and then used to characterize CD137 protein expression in hematolymphoid tissues by immunofluorescence, immunohistochemistry and tissue microarrays.
Results: In normal hematopoietic tissues, CD137 protein is expressed by FDC in GC and scattered paracortical T cells, but not by normal GC B cells, bone marrow progenitor cells or maturing thymocytes. Most mature B cell lymphomas lack CD137 expression in tumor cells, although a significant proportion show variable numbers of CD137-positive infiltrating host cells. Classical Hodgkin lymphoma cells but not nodular lymphocyte predominant Hodgkin lymphoma cells, exhibit strong and consistent expression of CD137. CD137 is expressed by mature T-cell and extranodal NK/T cell lymphomas and FDC neoplasms, but is not observed in histiocytic tumors, myeloid or lymphoid leukemias or plasma cell neoplasms.
|Tumor subtype||Total positive|
|Mature B cell lymphomas||0/435 (0%)|
|Mature T cell lymphomas||16/21 (76%)|
|Extranodal NK/T cell lymphoma||34/93 (35%)|
|Plasma cell neoplasms||0/158 (0%)|
|Classical Hodgkin lymphoma||179/208 (88%)|
|Lymphocyte predominant Hodgkin lymphoma||0/17 (0%)|
|Histiocytic neoplasms||0/20 (0%)|
|Follicular dendritic cell sarcoma||6/7 (86%)|
|Acute leukemias||0/25 (0%)|