CD137 is expressed in follicular dendritic cell tumors and in classical Hodgkin and T-cell lymphomas: diagnostic and therapeutic implications

Abstract

CD137 (also known as 4-1BB and TNFRSF9) is a member of the tumor necrosis factor receptor superfamily. Originally identified as a costimulatory molecule expressed by activated T cells and NK cells, CD137 is also expressed by follicular dendritic cells, monocytes, mast cells, granulocytes, and endothelial cells. Anti-CD137 immunotherapy has recently shown promise as a treatment for solid tumors and lymphoid malignancies in preclinical models. We defined the expression of CD137 protein in both normal and neoplastic hematolymphoid tissue. CD137 protein is expressed by follicular dendritic cells in the germinal center and scattered paracortical T cells, but not by normal germinal-center B cells, bone marrow progenitor cells, or maturing thymocytes. CD137 protein is expressed by a select group of hematolymphoid tumors, including classical Hodgkin lymphoma, T-cell and NK/T-cell lymphomas, and follicular dendritic cells neoplasms. CD137 is a novel diagnostic marker of these tumors and suggests a possible target for tumor-directed antibody therapy.

Figure 1

Expression of CD137 protein in normal human hematopoietic tissues. A: Section of normal reactive human tonsil stained with antibodies to CD137 (red; cytoplasm and cell membrane) and CD3 (green; cell membrane). DAPI (blue) was used as a nuclear counterstain. B: Section of normal reactive human tonsil stained with antibodies to CD137 (red) and OCT-2 (green; nuclear). C: Section of normal human tonsil stained with antibody to CD21. D: Section of normal human tonsil stained with antibody to CD137. E: Section of normal human thymus stained with anti-CD137 antibody. F: Section of normal human spleen stained with anti-CD137 antibody. Original magnification: ×100 (A); ×400 (B–D); ×200 (E and F); ×600 (insets).

Figure 2

CD137 is expressed by FDC tumors and classical Hodgkin lymphoma. A–D: Immunohistochemical stain for CD137 on paraffin-embedded tissue sections of FDC tumor (A), Langerhans cell histiocytosis (LCH) (B), classical Hodgkin lymphoma (CHL) (C), and nodular lymphocyte predominant Hodgkin lymphoma (NLPHD) (D). E and F: Sections of classical Hodgkin lymphoma stained with antibodies to CD137 (red; cytoplasm and cell membrane) and CD3 (green; cell membrane); DAPI (blue) was used as a nuclear counterstain. G: Section of classical Hodgkin lymphoma stained with antibodies to CD137 (red; cytoplasm and cell membrane) and CD3 (green; cell membrane), with DAPI (blue) as a nuclear counterstain, visualized using confocal microscopy. Original magnification: ×400 (A–G); ×900 (inset, C); ×600 (inset, D).

Figure 3

CD137 expression by B-, T-, and NK-cell-derived lymphomas. Immunohistochemical stains for CD137 on paraffin-embedded tissue sections of follicular lymphoma (FL) (A), diffuse large B-cell lymphoma (DLBCL) (B), and chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) (C) show lack of expression of CD137 in tumor cells. In contrast to B-cell lymphomas, peripheral T-cell lymphoma not otherwise specified (PTCL) (D), angioimmunoblastic T-cell lymphoma (AITL) (E), ALK⁺ anaplastic large cell lymphoma (ALCL) (F), CD30⁺ mycosis fungoides (MF) (G), and extranodal NK/T-cell lymphoma, nasal type (NK) (H), show tumor cell staining for CD137. Original magnification, ×400.

Figure 4

Detection of tumor cell CD137 expression by flow cytometry. A–F: A case of ALK⁻ anaplastic large cell lymphoma was stained with H&E (A) and antibodies to CD8 (B), CD4 (C), CD30 (D), ALK1 (E), and CD137 (F). The lymphoma cells showed positivity for CD8, CD30, and CD137. G: Flow cytometric evaluation of CD137 expression showed lack of CD137 expression by CD20⁺ B cells and CD4⁺ T cells, but detectable expression of CD137 in a proportion (18.5 %) of CD8⁺ tumor T cells. Original magnification, ×600.