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Cancer Res. 2017 Nov 1;77(21):5989-6000. doi: 10.1158/0008-5472.CAN-17-0610. Epub 2017 Sep 18.

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

Author information

1
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea.
2
Biomedical Research Center, Ulsan University Hospital, College of Medicine, University of Ulsan, Ulsan, Republic of Korea.
3
Institute of Oral Biology, School of Dentistry, Kyung Hee University, Seoul, Republic of Korea.
4
Department of Microbiology, College of Medicine, Inje University, Pusan, Republic of Korea.
5
Utilex, Seoul, Republic of Korea.
6
Biomedical Research Center, Ulsan University Hospital, College of Medicine, University of Ulsan, Ulsan, Republic of Korea. bkwon@mail.ulsan.ac.kr hrcho@uuh.ulsan.kr.
7
Department of Surgery, Ulsan University Hospital, University of Ulsan, Ulsan, College of Medicine, Republic of Korea.
8
School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea. bkwon@mail.ulsan.ac.kr hrcho@uuh.ulsan.kr.

Abstract

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.

PMID:
28923858
DOI:
10.1158/0008-5472.CAN-17-0610
[Indexed for MEDLINE]
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