Anti-CD137 Suppresses Tumor Growth by Blocking Reverse Signaling by CD137 Ligand

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-11, Vol.77 (21), p.5989-6000
• Main Authors: Kang, Sang W, Lee, Sang C, Park, So H, Kim, Juyang, Kim, Hyeon H, Lee, Hyeon-Woo, Seo, Su K, Kwon, Byoung S, Cho, Hong R, Kwon, Byungsuk
• Format: Article
• Language: English
• Subjects: 4-1BB Ligand - immunology; 4-1BB Ligand - metabolism; Animals; Antibodies; Antibodies, Monoclonal - immunology; Antibodies, Monoclonal - pharmacology; Antitumor activity; Cancer; Cancer immunotherapy; CD103 antigen; CD137 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Line, Tumor; Cytotoxicity; Dendritic cells; Dendritic Cells - immunology; Dendritic Cells - metabolism; Feedback loops; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - immunology; Immunomodulation; Immunosurveillance; Immunotherapy; Interferon-gamma - immunology; Interferon-gamma - metabolism; Interleukin 1; Interleukin 12; Ligands; Lymphocytes; Lymphocytes T; Macrophages; Macrophages - immunology; Macrophages - metabolism; Mice; Mice, Inbred BALB C; Mice, Knockout; Neoplasms - genetics; Neoplasms - immunology; Neoplasms - metabolism; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; T-Lymphocytes, Cytotoxic - immunology; T-Lymphocytes, Cytotoxic - metabolism; Tumor Burden - drug effects; Tumor Burden - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - genetics; Tumor Necrosis Factor Receptor Superfamily, Member 9 - immunology; Tumor Necrosis Factor Receptor Superfamily, Member 9 - metabolism; Tumors; γ-Interferon
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-17-0610

CD137 (4-1BB) is a T-cell costimulatory molecule, and agonstic CD137 antibodies are currently being evaluated in the clinic as cancer immunotherapy. Recently, it was found that CD137 mice or mice injected with agonistic anti-CD137 antibodies exhibit heightened antitumor responses, contrary to expectations based on other knowledge of CD137 function. Here, we report findings related to reverse signaling by CD137 ligand (CD137L) in antigen-presenting dendritic cells (DC) in tumors that address these paradoxical results. Specifically, CD137L suppressed intratumoral differentiation of IL12-producing CD103 DC and type 1 tumor-associated macrophages (TAM). Differentiation of these cell types is important because they are required to generate IFNγ-producing CD8 cytotoxic T lymphocytes (Tc1). Notably, CD137L blockade increased levels of IL12 and IFNγ, which promoted intratumoral differentiation of IFNγ-producing Tc1, IL12-producing CD103 DC, and type 1 TAM within tumors. Our results offer an explanation for the paradoxical effects of CD137 blockade, based on differential immunomodulatory effects of CD137 signaling and reverse signaling in T cells and DC, respectively. Further, they show how CD137L blockade can seed a forward-feedback loop for activation of CD103 DC/type 1 TAM and Tc1 that can create a self-perpetuating cycle of highly effective immunosurveillance. .