Reengineering dendritic cell-based anti-cancer vaccines

Despite initial enthusiasm, dendritic cell (DC)-based anticancer vaccines have yet to live up to their promise as one of the best hopes for generating effective anti-tumor immunity. One of the principal reasons for the generally disappointing results achieved thus far could be that the full potential of DCs has not been effectively exploited.

Here, we argue that dramatic improvements in vaccine efficacy will probably require a careful re-evaluation of current vaccine design. The formulation of new strategies must take into account the natural history of DCs, particularly their role in helping the immune system deal with infection. Equally critical is the emerging importance of soluble factors, notably interleukin-12, in modulating the quality of immune responses.

Vaccines should also be designed to recruit helper T cells and antibody-producing Bcells rather than simply cytotoxic T lymphocytes. Finally, the judicious selection of tumor, target antigen, and disease stage best suited for treatment should serve as the foundation of trial designs. Our discussion addresses a recent clinical vaccine trial to treat early breast cancer, where many elements of this new strategy were put into practice.

A Novel Dendritic Cell-Based Immunization

The immune system has traditionally been divided into two parts; the innate and the adaptive. The innate immune system’s components include monocytes, macrophages, granulocytes, NK and dendritic cells (DC). The adaptive immune system is composed of antibody-producing B lymphocytes, as well as CD4pos helper T cells and CD8pos cytotoxic T cells. These cells work together to sense, control and eliminate infection. Agents of innate immunity identify microbes through special pattern recognition receptors that sense biochemical structures (usually non-proteins) common to broad classes of potential pathogens

(1). On the other hand, T and B lymphocytes specialize in responding against antigens (usually proteins) specific to the individual species of microbe. DCs have a unique role in that they form a critical bridge between innate and adaptive immunity. Pattern recognition proteins belonging to the Toll-like family of transmembrane receptors (2) induce a maturation and migration program whereby various DC populations, including monocytederived DCs, convey peripherally-acquired proteins to T cells located in the regional draining lymph nodes (3).

The DCs “present” the microbial antigens to T cells in the form of processed peptides complexed with self major histocompatibility proteins (4). This supplies an important signal (signal 1) to T cells that, along with maturation-enhanced co-stimulatory molecule (CD80, CD86) expression (signal 2), can fully activate T cells (5). DCs and some other accessory cells can supply so-called “third signals” (6) that often are expressed in the form of soluble factors, for example, IL-12, IL-23, IL-6 and TGF-beta. Such signals can profoundly influence helper T cell development toward discrete functional phenotypes that include IFN-γ-secreting Th1, IL-17- secreting Th17, as well as anti-inflammatory Treg that produce TGF-beta and IL-10 (7–10).

In many instances, the precise combination of activation signals received by DC dictates whether individual 3rd signal agents will be produced, and hence which Th phenotypes will be selectively induced by the DC (11). Although the immune system evolved primarily to deal with infections, it may be possible to direct it against malignancies. An ideal strategy for inducing anti-tumor immunity must successfully accomplish several goals-some of which are overlapping with traditional antimicrobial vaccines, but others unique to the particular requirements of effective anti-tumor immunity. For example, an effective anti-tumor vaccine must overcome the immune system’s natural tendency to resist the development of strong immunity against self-proteins (i.e. tolerance).

It must also generate immunity of a quality and intensity likely to reduce or eliminate tumor burdens. In the case of therapeutic vaccines, immunity must be effectively induced when disease is already firmly established. Finally, such induced immunity should be durable, so that possible tumor recurrences can be suppressed for long per periods postimmunization.

Extracellular ATP and Toll-Like Receptor

Dendritic cells (DC) are the most potent known antigenpresenting cells and are primarily responsible for sensitizing naıve T cells to antigen. DC activate T cells by supplying antigenic (signal 1) and co-stimulatory (signal 2) signals as well as an additional set of ‘‘third signals’’ that can profoundly affect T cell function [1].

For example, if the cytokine interleukin-12 (IL-12) is present during Th sensitization it is likely that Th1 polarization will occur, resulting in T cells that produce high levels of IFN-c and correspondingly less (or no) IL-4 and IL-5 [2]. Such cells can be highly effective for dealing with some intracellular parasites [3].On the other hand, the cytokines IL-23, IL-6, TGF-b and IL-1b have each been implicated by various groups [4–9] in promoting the development of IL-17-producing Th17 cells.

These Th17 cells appear highly effective against extracellular bacteria, particularly those that colonize mucosal surfaces [10], and have also been implicated in chronic inflammatory pathology associated with some autoimmune diseases [11,12]. Additional cytokines contribute to the development of other key Th phenotypes including Th2 and Treg [12,13]. It has therefore become increasingly clear that these individual Th phenotypes represent adaptations for dealing with particular types of infection, or otherwise regulating immune responses. In contrast, dysregulation of these differentiation programs could result in ineffective immune responses against pathogens, debilitating autoimmune pathologies, or perhaps even promotion of carcinogenesis [14].

Dendritic Cell-Induced Th1 and Th17 Cell Differentiation for Cancer Therapy

The success of cellular immunotherapies against cancer requires the generation of activated CD4+ and CD8+ T-cells. The type of T-cell response generated (e.g., Th1 or Th2) will determine the efficacy of the therapy, and it is generally assumed that a type-1 response is needed for optimal cancer treatment. IL-17 producing T-cells (Th17/Tc17) play an important role in autoimmune diseases, but their function in cancer is more controversial.

While some studies have shown a pro-cancerous role for IL-17, other studies have shown an anti-tumor function. The induction of polarized T-cell responses can be regulated by dendritic cells (DCs). DCs are key regulators of the immune system with the ability to affect both innate and adaptive immune responses. These properties have led many researchers to study the use of ex vivo manipulated DCs for the treatment of various diseases, such as cancer and autoimmune diseases.

While Th1/Tc1 cells are traditionally used for their potent anti-tumor responses, mounting evidence suggests Th17/Tc17 cells should be utilized by themselves or for the induction of optimal Th1 responses. It is therefore important to understand the factors involved in the induction of both type-1 and type-17 T-cell responses by DCs.

Rationale for a Multimodality Strategy to Enhance the Efficacy of Dendritic Cell-Based Cancer Immunotherapy

Dendritic cells (DC), master antigen-presenting cells that orchestrate interactions between the adaptive and innate immune arms, are increasingly utilized in cancer immunotherapy. Despite remarkable progress in our understanding of DC immunobiology, as well as several encouraging clinical applications – such as DC-based sipuleucel-T for metastatic castration-resistant prostate cancer – clinically effective DC-based immunotherapy as monotherapy for a majority of tumors remains a distant goal. The complex interplay between diverse molecular and immune processes that govern resistance to DC-based vaccination compels a multimodality approach, encompassing a growing arsenal of anti-tumor agents which target these distinct processes and synergistically enhance DC function. These include antibody-based targeted molecular therapies, immune checkpoint inhibitors, therapies that inhibit immunosuppressive cellular elements, conventional cytotoxic modalities, and immune potentiating adjuvants. It is likely that in the emerging era of “precision” cancer therapeutics, tangible clinical benefits will only be realized with a multifaceted – and personalized – approach combining DC-based vaccination with adjunctive strategies.

Affiliation

Division of Endocrine and Oncologic Surgery, Department of Surgery, University of Pennsylvania Perelman School of Medicine , Philadelphia, PA , USA ; Rena Rowen Breast Center, Hospital of the University of Pennsylvania , Philadelphia, PA , USA.