Anti-CD137 Suppresses Tumor Growth by Blocking Reverse Signaling by CD137 Ligand
| العنوان: | Anti-CD137 Suppresses Tumor Growth by Blocking Reverse Signaling by CD137 Ligand |
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| المؤلفون: | So H. Park, Sang W. Kang, Hong R. Cho, Juyang Kim, Sang-Chul Lee, Hyeon H Kim, Su-Kil Seo, Hyeon-Woo Lee, Byungsuk Kwon, Byoung S. Kwon |
| المصدر: | Cancer Research. 77:5989-6000 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2017. |
| سنة النشر: | 2017 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Cell type, medicine.medical_treatment, CD8-Positive T-Lymphocytes, Biology, Interferon-gamma, Tumor Necrosis Factor Receptor Superfamily, Member 9, 03 medical and health sciences, Cancer immunotherapy, Cell Line, Tumor, Neoplasms, medicine, Animals, Cytotoxic T cell, Mice, Knockout, Mice, Inbred BALB C, Macrophages, CD137, Antibodies, Monoclonal, Cell Differentiation, Dendritic Cells, Tumor Burden, Blockade, Gene Expression Regulation, Neoplastic, Immunosurveillance, 4-1BB Ligand, 030104 developmental biology, Oncology, Immunology, Cancer research, Interleukin 12, CD8, Signal Transduction, T-Lymphocytes, Cytotoxic |
| الوصف: | 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. Cancer Res; 77(21); 5989–6000. ©2017 AACR. |
| تدمد: | 1538-7445 0008-5472 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::177a9bcc0bcc1cdd4caef6968b06108b https://doi.org/10.1158/0008-5472.can-17-0610 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....177a9bcc0bcc1cdd4caef6968b06108b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15387445 00085472 |
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