Bone marrow cells of WT or CD137-/- mice were cultured in plates coated with human IgG1 or CD137-Fc¬ in the presence of murine Flt3L for 9 d. IFN-gamma and GM-CSF were added, and cells were cultured for an additional 2 d to polarize differentiated DCs toward CD103+ subsets. CD103+ DCs (middle panel) were gated from CD11c+F4/80- cells (upper panel). Macrophages are categorized as F4/80+CD11b+CD11c+ or F4/80+CD11b+CD11c- cells (upper and lower panels).
ARTICLE 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.
