Clinical Implications of Co-Inhibitory Molecule Expression in the Tumor Microenvironment for DC Vaccination: A Game of Stop and Go

Abstract

The aim of therapeutic dendritic cell (DC) vaccines in cancer immunotherapy is to activate cytotoxic T cells to recognize and attack the tumor. T cell activation requires the interaction of the T cell receptor with a cognate major-histocompatibility complex-peptide complex. Although initiated by antigen engagement, it is the complex balance between co-stimulatory and co-inhibitory signals on DCs that results in T cell activation or tolerance. Even when already activated, tumor-specific T cells can be neutralized by the expression of co-inhibitory molecules on tumor cells. These and other immunosuppressive cues in the tumor microenvironment are major factors currently hampering the application of DC vaccination. In this review, we discuss recent data regarding the essential and complex role of co-inhibitory molecules in regulating the immune response within the tumor microenvironment. In particular, possible therapeutic intervention strategies aimed at reversing or neutralizing suppressive networks within the tumor microenvironment will be emphasized. Importantly, blocking co-inhibitory molecule signaling, often referred to as immune checkpoint blockade, does not necessarily lead to an effective activation of tumor-specific T cells. Therefore, combination of checkpoint blockade with other immune potentiating therapeutic strategies, such as DC vaccination, might serve as a synergistic combination, capable of reversing effector T cells immunosuppression while at the same time increasing the efficacy of T cell-mediated immunotherapies. This will ultimately result in long-term anti-tumor immunity.

Keywords: DC vaccination; cancer treatment; checkpoint blockade; tumor microenvironment; tumor-specific T cells.

Figure 1

Dendritic cell vaccination is counteracted by host immunosuppressive mechanisms. Monocytes or natural occurring dendritic cells are isolated from the peripheral blood of the patient, loaded with tumor antigens, and subsequently matured. These activated DCs are re-infused into the patient and migrate to the lymph node to encounter and interact with naïve T cells in order to induce the activation of effector T cells. DC-mediated T cell activation is regulated by four signals: (I) interaction between TCR on T cells and MHC:peptide complex, (II) co-stimulation via CD28 and CD80/86 expressed on T cells and DCs respectively, (III) secretion of pro-inflammatory cytokines such as IFNs and IL-12, and (IV) release of DC-processed metabolites. These activated CD8⁺ cytotoxic T cells and CD4⁺ T helper cells migrate to the tumor site where they are eventually neutralized by the immunosuppressive nature of the tumor microenvironment due, for instance, to the expression of co-inhibitory molecules.

Figure 2

Stimulatory and inhibitory molecules expressed in the tumor microenvironment targeted for therapeutic intervention. Schematic visualization of stimulatory and inhibitory receptors expressed on T cells and on various tumor cells. Specific monoclonal antibodies are in development that either function as agonists, enhancing T cell activation, or antagonist, blocking T cell inhibitory molecules. *(ClinicalTrials.gov identifier: NCT00658892).

Figure 3

Cytotoxic T lymphocyte-associated antigen-4 blockade restores T cell activation. After recognition of MHC:peptide complex by the TCR, the second signal for T cell activation is provided by binding of CD80 or 86 to CD28 on the T cells. This interaction leads to cell surface expression of CTLA-4, which has a higher affinity for CD80/86, thus interrupting the activation signal. Additionally, the signal delivered via CTLA-4 down-regulates T cell function and inhibits excessive expansion of activated T cells. Anti-CTLA-4 monoclonal antibodies bind to CTLA-4, and block the interaction with CD28, which is again free to interact with CD80/86, prolonging T cell activation and amplifying T cell-mediated immunity against tumors.

Figure 4

Programed cell death-1 pathway blockade promotes tumor-specific T cell activation and elimination of tumor cells. The PD-1 pathway operates on two different levels, regulating both T cell activation by DCs and the effector function of antigen-specific T cells. PD-1 pathway blockade by monoclonal antibodies directed against PD-1, or its ligands, promotes T cell activation by shifting the balance of signals delivered by the DC from suppressive to activating. In the tumor microenvironment, tumor-specific T cells recognize tumor cells but are subsequently inactivated by the expression of PD-L1 or PD-L2 on the tumor cell, inducing tolerance and anergy. When rescued, by blocking the PD-1 pathway, T cells recognize antigen in the periphery and, in the absence of PD-1 engagement, they assume full effector function and eliminate tumor cells.

Figure 5

Combining DC vaccination with immune checkpoint blockade. DC vaccination of cancer patients leads to the induction of tumor-specific T cells that migrate to the tumor microenvironment. PD-1 pathway blockade synergistically potentiates the effects of DC vaccination by blocking PD-1/PD-L1 induced immunosuppression leading to enhanced tumor cell killing.