The TNFRs OX40, 4-1BB, and CD40 as targets for cancer immunotherapy

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T cell-mediated rejection of tumors requires signals from the T cell receptor and co-stimulatory molecules to license effector functions of tumor-antigen specific T cells. There is also an array of immune suppressive mechanisms within the tumor microenvironment that can suppress anti-tumor immunity. The use of monoclonal antibodies to overcome this suppression and/or enhance tumor-antigen specific T cell responses has shown promise in clinical trials. In particular, targeting co-stimulatory members of the tumor necrosis factor receptor (TNFR) family with agonist Abs enhances T cell function, which has led to encouraging therapeutic results in cancer-bearing hosts. These encouraging data establish TNFRs as important targets for enhancing tumor-specific immune responses in mice and man. This review will focus on agonists that target the TNFRs OX40, 4-1BB, and CD40.

Highlights

Agonist antibodies to TNFR molecules can promote tumor regression. ► TIL express TNFR molecules but the endogenous ligand is often limited. ► Clinical trials targeting TNFR molecules are underway and show promise. ► Combination therapies directed against multiple TNFR molecules may be advantageous.

Introduction

Targeting co-stimulatory and co-inhibitory receptors expressed by immune cells is a promising new approach for treating cancer. The recent FDA approval of the monoclonal antibody (mAb) against the inhibitory molecule CTLA-4 (ipilumimab) demonstrates the proof of principle that enhancing T cell function can have therapeutic effects in cancer patients [1••]. This study provides the foundation for many other monoclonal Ab therapies that are currently in clinical development. Some of these mAbs target members of immune cell surface molecules that are within the tumor necrosis factor (TNF) and TNF receptor superfamily (TNFRSF). There are approximately 50 members of this protein family that are both membrane bound and soluble and are expressed by cells of the immune system. When these proteins are ligated either by their cognate receptor or by agonist antibodies, a wide range of cellular outcomes has been reported ranging from cell differentiation, proliferation, apoptosis and survival to increased production of cytokines and chemokines [2, 3, 4, 5, 6, 7]. In addition, the unique expression of some of the TNFRSF members on antigen-specific T cells has made these molecules ideal targets for novel immunotherapies.

Immunotherapy has been proposed as an effective mechanism for controlling tumor growth since the late 1800s [8]. In the past few decades, the generation of monoclonal antibodies that target either immune-stimulating receptors or inhibitory receptors has shown to increase anti-tumor immunity in cancer-bearing hosts leading to therapeutic responses. The general premise regarding these therapies is that cancer-bearing hosts have T cells that are specific for tumor Ags residing in their body; however, their function is suppressed by the tumor microenvironment. Moreover, the frequency of tumor antigen specific cells is also speculated to be limited. Therefore, these immune stimulating Abs help to overcome this immune suppression by increasing the frequency and function of antigen presenting cells (APCs) and T cells, which ultimately leads to tumor regression [9]. Many of the TNFR family members have been identified as potential immunotherapy targets.

Optimal activation of naïve T cells requires a strong T cell receptor peptide antigen-MHC interaction along with engagement of costimulatory molecules expressed by APCs [10]. In the absence of these costimulatory signals, activated naïve T cells die or are rendered anergic [11]; thus costimulation is indispensible for a functional T cell response. Many costimulatory receptors have been described but signals from CD28, a costimulatory molecule constitutively expressed on naïve T cells, is indispensable for T cell effector function and expansion.

In addition to CD28, there are a number of other costimulatory proteins that are required to generate optimal effector and memory T cells following antigen encounter. Several of these costimulatory proteins are members of the TNFR superfamily. Initially described to be expressed on activated T and B lymphocytes and APCs, ligation of some of these receptors is shown to promote cell division and survival, differentiation, maturation, and provide signals directly to T cells (Table 1). Because of the unique T cell activating features of these receptors, many groups have targeted TNFRs with agonist mAbs to enhance lymphocyte function, particularly in the context of tumor immunotherapy.

Distinct TNFR subtypes have been described, ones that contain a death domain (DD) (i.e. FAS, DR5, TNFRI), decoy receptors that do not signal, and receptors that need adaptor molecules to signal, the latter will be the focus of this review. The TNF receptors that need adaptor molecules to signal use intracellular TNF receptor-associated factor (TRAF) proteins that interact with the cytoplasmic tail of these TNFRs. This in turn activates downstream signaling of NK-κB, activation of mitogen-activated protein 3 kinase, and PI3-k signaling to promote effector T cell recruitment and function such as cell survival, proliferation, and activation [12, 13].

In this review, we focus on the role of the immune activating TNFRSF members expressed predominantly by T cells as immunotherapeutic targets for an array of cancer malignancies. We will briefly discuss the biology of these receptors and their ability to activate the immune system and then present data on the pre-clinical and clinical findings of targeting TNFRSF members for immunotherapy of cancer. In particular, we will discuss CD40, CD134 (OX40), and CD137 (4-1BB) in detail.

Section snippets

OX40 background and tumor immunotherapy

OX40 was initially described as a T cell activation marker on rat CD4 T cells [14] and shown later to be upregulated upon TCR engagement [15]. OX40 signaling can promote co-stimulatory signals to T cells leading to enhanced cell proliferation, survival, effector function and migration [3, 16]. The ligand for OX40, OX40L, is predominantly expressed on APCs and its expression can be induced via CD40 and mast cell signaling, toll like receptors (TLRs), as well as inflammatory cytokines. In

4-1BB

The first of the TNFR family members to be identified as a possible immunotherapy target was 4-1BB (also known as CD137) [34]. 4-1BB, expressed on activated T cells (Figure 1), NK cells, and a number of other activated cells of hematopoietic and non-hematopoietic origin including endothelial cells of some tumors, binds to its ligand 4-1BBL expressed by activated DCs, B cells, and macrophages. This interaction leads to a co-stimulatory signal that promotes the upregulation of anti-apoptotic

CD40

CD40 is constitutively expressed on APCs and ligation promotes functional maturation leading to an increase in antigen presentation and cytokine production, and a subsequent increase in the activation of antigen specific T cells (Figure 1). Initial studies using an agonist CD40 antibody showed increased cytotoxic lymphocyte (CTL) responses against poorly activating tumor antigens [48, 49] and promoted effector function of cytotoxic T cells tolerized by tumor antigens [50]. Thus, targeting CD40

Conclusions and future perspectives

The promise of immunotherapy for the treatment of cancer has been confirmed by the success reported in recent clinical trials in which co-inhibitory molecules have been targeted [1••, 59••, 60••]. While these therapies increased the anti-tumor immune responses in patients with a range of malignancies, efficacy often correlated with the immunogenicity of the tumor. Therefore, we propose that successful immunotherapeutic approaches for poorly immunogeneic tumors will require combination with

Conflict of interest

A.D. Weinberg has issued patents regarding the use of OX40 agonists to treat cancer patients.

A.E. Moran and M. Kovacsovics-Bankowski declare no conflict of interest related to this work.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Supported by NIH grants RO1 CA102577 and CA122701 (M.K.B, A.D.W), DOD grant W81XWH-11-1-0345 (A.D.W.), and NIH T32 AI78903 training fellowship (A.E.M.). The authors wish to thank Walter J. Urba for critical reading of this manuscript.

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