4-1BB Agonists: Multi-Potent Potentiators of Tumor Immunity

Abstract

Immunotherapy is a rapidly expanding field of oncology aimed at targeting, not the tumor itself, but the immune system combating the cancerous lesion. Of the many approaches currently under study to boost anti-tumor immune responses; modulation of immune co-receptors on lymphocytes in the tumor microenvironment has thus far proven to be the most effective. Antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte antigen-4 (CTLA-4) has become the first FDA approved immune checkpoint blockade; however, tumor infiltrating lymphocytes express a diverse array of additional stimulatory and inhibitory co-receptors, which can be targeted to boost tumor immunity. Among these, the co-stimulatory receptor 4-1BB (CD137/TNFSF9) possesses an unequaled capacity for both activation and pro-inflammatory polarization of anti-tumor lymphocytes. While functional studies of 4-1BB have focused on its prominent role in augmenting cytotoxic CD8 T cells, 4-1BB can also modulate the activity of CD4 T cells, B cells, natural killer cells, monocytes, macrophages, and dendritic cells. 4-1BB's expression on both T cells and antigen presenting cells, coupled with its capacity to promote survival, expansion, and enhanced effector function of activated T cells, has made it an alluring target for tumor immunotherapy. In contrast to immune checkpoint blocking antibodies, 4-1BB agonists can both potentiate anti-tumor and anti-viral immunity, while at the same time ameliorating autoimmune disease. Despite this, 4-1BB agonists can trigger high grade liver inflammation which has slowed their clinical development. In this review, we discuss how the underlying immunobiology of 4-1BB activation suggests the potential for therapeutically synergistic combination strategies in which immune adverse events can be minimized.

Keywords: 4-1BB; CD137; co-stimulation; combination therapy; immunotherapy.

Figure 1

A multi-potent role for 4-1BB targeted immunotherapy. 4-1BB agonist therapies elicit diverse immune effector responses on both the innate and adaptive immune arms. The most potent of responses stimulate CD8⁺ cytotoxic T cells to proliferate and increase their effector potential through increased interferon gamma production and expression of multiple granzymes. CD4⁺ effector T cells can also be stimulated to expand and produce pro-inflammatory cytokines. The role of 4-1BB stimulation on regulatory T cells, however, is controversial. 4-1BB agonist therapy may either inhibit differentiation of conventional effector cells into Tregs while also inhibiting Treg suppression, or, conversely, maintain Treg expansion and suppressive capacity. NK cells also benefit from 4-1BB agonist therapy. Not only can α4-1BB antibodies stimulate antibody-dependent cell-mediated cytotoxicity through Fc/FcR interactions, but activated NK cells express 4-1BB to become targets of therapy. Additionally, cells of the myeloid lineage upregulate 4-1BB upon activation. 4-1BB agonists targeting dendritic cells induce DC maturation and antigen presentation. In addition, α4-1BB stimulated DCs begin to express IL-12 and IL-27 as well as the enzyme IDO to modulate T cell function. 4-1BB⁺ macrophages can also be stimulated to increase antigen presentation and produce IL-8 as well as IDO.