Dendritic-cell-based therapeutic cancer vaccines

Abstract

The past decade has seen tremendous developments in novel cancer therapies through the targeting of tumor-cell-intrinsic pathways whose activity is linked to genetic alterations and the targeting of tumor-cell-extrinsic factors, such as growth factors. Furthermore, immunotherapies are entering the clinic at an unprecedented speed after the demonstration that T cells can efficiently reject tumors and that their antitumor activity can be enhanced with antibodies against immune-regulatory molecules (checkpoint blockade). Current immunotherapy strategies include monoclonal antibodies against tumor cells or immune-regulatory molecules, cell-based therapies such as adoptive transfer of ex-vivo-activated T cells and natural killer cells, and cancer vaccines. Herein, we discuss the immunological basis for therapeutic cancer vaccines and how the current understanding of dendritic cell and T cell biology might enable the development of next-generation curative therapies for individuals with cancer.

Figure 1. Therapeutic vaccines act via dendritic cells to generate protective CD8⁺T cell immunity

Therapeutic vaccines are designed to elicit cellular immunity. In this goal, they are expected to prime new T cells as well as induce a transition from chronically activated non-protective CD8⁺ T cells to healthy CD8⁺ T cells able to i) generate cytotoxic T lymphocytes (CTLs) that reject cancer and ii) provide long-lived memory CD8⁺ T cells able to rapidly generate new effector T cells secreting cytotoxic molecules thereby preventing relapse. Numerous approaches to therapeutic vaccines that are being pursued are illustrated. Their common denominator is the action via DCs either randomly or specific targeting.

Figure 2. Dendritic cells play a central role in vaccination

The desired properties of vaccine-elicited CD8⁺ T cells include: i) high TCR affinity and high T cell avidity; ii) high levels of granzymes and perforin; iii) trafficking into the tumor and persistence in the tumor site; and iv) high proliferation potential. Naïve CD8⁺ T cells initiate a CTL differentiation program upon encounter with DCs presenting tumor-derived peptides via MHC class I. This is supported by co-stimulation mediated by CD80, CD70 and 4-1BB and by DC-derived cytokines such IL-15. XCR1 chemokine secreted by DCs facilitates the interaction with naïve CD8⁺ T cells. TGFβ expressed by DCs is critical for CD8⁺ T cells to express CD103 and acquire mucosal phenotype. CD8⁺ T cell differentiation, especially generation of memory, is dependent on the quality of CD4⁺ T cell help. The latter one is partially dependent on the IL-12 secreted by DCs. CD4⁺ T cells producing IFNγ and/or IL-21 can help CD8⁺ T cell expansion and differentiation. Tregs might play a critical role during the selection of high-avidity CD8⁺ T cells. This might be ascribed to the cross-talk between DCs and CD4⁺ T cells where CD4⁺ T cells control DC functions. There, Tregs can suppress DCs via IL-10 production and also regulate the production of chemokines, thereby limiting the interactions between DCs and low-avidity T cells. CD4⁺ T cells can also provide DC maturation signals via CD40.

Figure 3. The barriers for CD8⁺ T cell-mediated tumor rejection

The next generation vaccines must confront and address numerous barriers that CD8⁺ T cells face including: i) T cells access to the tumor site; ii) T cell intrinsic regulators, for example CD28-CTLA-4, PD1-PDL1; iii) T cell extrinsic regulators such as suppressor cells: Tregs, MDSCs or pro-tumor macrophages; tumor secreted suppressive factors including IL-10; and suppressive surface molecules including co-inhibitory molecules from B7 family.