Differential effects of agonistic 4-1BB (CD137) monoclonal antibody on the maturation and functions of hypoxic dendritic cells.

Abstract

Agonistic 4-1BB monoclonal antibody (mAb), a promising approach for tumor immunotherapy, has entered clinical trials for some tumors due to its immunostimulatory effects on immune cells. Hypoxia, the hallmark of tumor microenvironment, influences functions of immune cells including dendritic cells (DCs). It remains unestablished whether 4-1BB mAb takes effects on DCs in hypoxic microenvironment. This study aims to examine the role of agonistic 4-1BB mAb in the maturation and functions of murine hypoxic DCs. As expected, hypoxia suppressed the maturation and activation of DCs, as suggested by down-regulation of class II MHC, co-stimulatory molecules and proinflammatory cytokines. These inhibitory effects of hypoxia were partially reversed by triggering 4-1BB on DCs with agonistic mAb, as evidenced by elevated co-stimulatory molecules CD80, CD86, and proinflammatory cytokines such as IL-6, TNF-α. Unexpectedly, the ability of hypoxic DCs to stimulate CD4+T cell proliferation seemed not to be affected by agonistic 4-1BB mAb. These data demonstrate that agonistic 4-1BB mAb partially restores the phenotypic maturation and proinflammatory function of hypoxic DCs, but fails to rescue their ability to stimulate T cell response. Collectively, our study provides evidence on the efficiency of agonistic 4-1BB mAb in hypoxic microenvironment, deserving of further consideration for clinic application.