Integrating costimulatory agonists to optimize immune-based cancer therapies

Abstract

While immunotherapy for cancer has become increasingly popular, clinical benefits for such approaches remain limited. This is likely due to tumor-associated immune suppression, particularly in the advanced-disease setting. Thus, a major goal of novel immunotherapeutic design has become the coordinate reversal of existing immune dysfunction and promotion of specific tumoricidal T-cell function. Costimulatory members of the TNF-receptor family are important regulators of T-cell-mediated immunity. Notably, agonist ligation of these receptors restores potent antitumor immunity in the tumor-bearing host. Current Phase I/II evaluation of TNF-receptor agonists as single-modality therapies will illuminate their safety, mechanism(s) of action, and best use in prospective combinational immunotherapy approaches capable of yielding superior benefits to cancer patients.

Keywords: T cell; TNF-receptor; combinational therapeutics; costimulation; cytotoxic T cell; immunotherapy; regulatory T cell.

Figure 1. TNF-receptor-mediated immunomodulation contributing to the antitumor effects of agonist therapies

The antitumor activity of TNF receptor (TNFR)-based therapy is executed through activation signals (upper half) to effector and memory T cells, which create an initial wave of tumor killing mediated by CD8⁺ cytolytic T cells and the indirect tumoricidal activity of IFN-γ [147]. Antitumor immunity can also be enhanced at this stage by the abrogation of regulatory T cell (Treg) function. Priming signals (lower half) to naive T cells in the tumor-draining lymph node also contribute to the TNFR-mediated response by generating secondary, delayed waves of tumor-specific effector cells. CD4⁺ Th1 cells and NK and NKT cells play essential roles in both stages, via IFN-γ-dependent CD8⁺ T cell ‘help’ in the effector phase (upper half) or by ‘licensing’ dendritic cell-mediated priming of naive T cells (lower half). The central box represents a source of exogenously administered agonist reagents, as would be applied therapeutically. The impact of costimulatory molecules expressed naturally by host DC is purposely discounted in the current figure. Dominant routes of TNFR-dependent immunomodulation are indicated in bold; secondary actions are italicized. GITR: Glucocorticoid-induced TNF receptor; NK: Natural killer.