In-Depth with CD137

Contributed by Aliyah Weinstein, Ph.D.

CD137, also known as 4-1BB, ILA, and TNFRSF9, is a member of the TNF family that was originally identified through genetic screens as being expressed on activated T cells1. CD137 is expressed on transitional CD45RA+ CD45RO+ T cells2 and activated CD8+ and CD4+ T cells3,4. It can be used as a marker for CD8+ T cells that are antigen-experienced. CD137 can also be expressed on dendritic cells, where ligation promotes cell survival and activation, and increases the duration of contact between dendritic cells and T cells5,6. Signaling through CD137 on T cells with its ligand, 4-1BBL or TNFSF9, expressed on professional antigen presenting cells including B cells, dendritic cells, and macrophages7 results in increased proliferation, increased secretion of IL-2 and interferon gamma, and a greater capacity to kill target cells4. 4-1BBL can also be expressed on T cells, and interact with CD137 on the surface of the same cell to promote an immunoregulatory T cell phenotype8. Outside of the canonical antigen presenting cell-T cell axis, CD137 has also been observed to be expressed on NK cells, NKT cells, and gamma delta T cells in the immune compartment, and endothelial cells, neural cells and osteoclasts9.

CD137 is implicated in many disease processes. Its widespread expression in the tumor microenvironment makes CD137 an optimal target for therapy, while its expression on cells throughout the body may also lead to adverse side effects. An early clinical study of patients with HIV indicated that a higher frequency of CD8+ T cells isolated from these patients express CD137 than CD8+ T cells isolated from healthy donors. Crosslinking of CD137 on CD4+ T cells from HIV+ donors increased replication of the HIV virus10 despite an increased level of cell surface CD137 being associated with antiretroviral treatment and a decrease in viral burden11. In the cancer setting, CD137 is expressed on the surface of many human tumor cell lines and primary tumors including cervical cancer, colon cancer, rectal cancer, and lung cancer12,13. In the tumor microenvironment, CD137 expression was predominantly found on the vasculature13. Because of its pervasive expression across tumor cell types, CD137 is a target of immunotherapy for cancer14. It was first elucidated as such when it was observed that agonistic antibodies against CD137, which activate CD8+ and CD4+ T cells in the tumor microenvironment, could eradicate both poorly and highly immunogenic tumors in a mouse model15. Since then, agonistic antibodies targeting 4-1BB has proven effective as an adjuvant therapy to dendritic cell vaccines16,17, IL-12-based gene therapy18, and chemotherapy19 for the treatment of a variety of murine tumor models including B16-F10 melanoma, MC38 colon carcinoma, and the renal cancer model Renca. Numerous clinical trials exploring the efficacy of targeting CD137 in combination with other checkpoint blockade therapies have been investigated; however, many were terminated due to adverse events including liver inflammation and neutropenia9,20,21. The efficacy of lowering the dose of anti-CD137 antibody, and the combination with other checkpoint blockade therapies, is under investigation.

 

 

Detection of Human CD137 in FFPE tonsil by IHC. Antibody: Rabbit anti-CD137 recombinant monoclonal [BLR051F] (A700-051). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of Human CD137 in FFPE tonsil by IHC. Antibody: Rabbit anti-CD137 recombinant monoclonal [BLR051F] (A700-051). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.


 

 
Detection of human CD137 in FFPE HDLM-2 cells by ICC. Antibody: Rabbit anti-CD137 recombinant monoclonal [BLR051F] (A700-051). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

Detection of human CD137 in FFPE HDLM-2 cells by ICC. Antibody: Rabbit anti-CD137 recombinant monoclonal [BLR051F] (A700-051). Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P). Substrate: DAB.

 

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