Betting on improved cancer immunotherapy by doubling down on CD134 and CD137 co-stimulation

Abstract

The ability of T cells to recognize a vast array of antigens enables them to destroy tumor cells while inflicting minimal collateral damage. Nevertheless, tumor antigens often are a form of self-antigen, and thus tumor immunity can be dampened by tolerance mechanisms that evolved to prevent autoimmunity. Since tolerance can be induced by steady-state antigen-presenting cells that provide insufficient co-stimulation, the exogenous administration of co-stimulatory agonists can favor the expansion and tumoricidal functions of tumor-specific T cells. Agonists of the co-stimulatory tumor necrosis factor receptor (TNFR) family members CD134 and CD137 exert antitumor activity in mice, and as monotherapies have exhibited encouraging results in clinical trials. This review focuses on how the dual administration of CD134 and CD137 agonists synergistically boosts T-cell priming and elaborates a multi-pronged antitumor immune response, as well as how such dual co-stimulation might be translated into effective anticancer therapies.

Keywords: CD134; CD137; CD4 T cell; dual costimulation; immunotherapy.

Figure 1. Co-stimulatory agonists enable T cells responding to tolerogenic tumor antigens to undergo expansion and effector differentiation. (A) Pathogen-associated molecular patterns (PAMPs) activate dendritic cells (DCs) presenting microbial peptides to express cytokines and co-stimulatory ligands that program T-cell expansion and effector differentiation. (B) In steady-state conditions, DCs acquire and present tumor antigens, but the absence of PAMPs results in the sub-optimal expression of cytokines and co-stimulatory ligands, causing cognate tumor-specific T cells to undergo tolerization. (C) CD40 agonists can activate DCs presenting tumor antigens to express cytokines and co-stimulatory ligands that program T-cell expansion and effector differentiation. (D) Agonists to co-stimulatory receptors program T cells responding to tumor antigens presented by steady-state DCs to undergo expansion and effector differentiation. A potential advantage of the approach described in (D), as compared with that depicted in (C), is that potentially toxic cytokines produced by DCs such as IL-12 are likely to be elaborated in much lower amounts.

Figure 2. Dual co-stimulation administered following androgen ablation may be an effective combination therapy to treat prostate cancer. Top, prostate tumor antigens presented by steady-state dendritic cells (DCs) in the draining lymph node program prostate-specific T cells to undergo tolerization. Bottom, androgen ablation induces a state of minimal residual disease by causing the majority of tumor cells to undergo cell death. Dual co-stimulation therapy may program prostate-specific T cells to expand, acquire effector functions, and eliminate the residual tumor. Since androgen ablation also induces the regeneration of the aged thymus, these prostate-specific T cells may be naïve recent thymic emigrants (green). Dual co-stimulation may also engage previously tolerized prostate-specific T cells (gray) since CD134 agonists can reverse pre-existing T cell anergy.