MODULATING CO-STIMULATION DURING ANTIGEN PRESENTATION TO ENHANCE CANCER IMMUNOTHERAPY

Abstract

One of the key roles of the immune system is the identification of potentially dangerous pathogens or tumour cells, and raising a wide range of mechanisms to eliminate them from the organism. One of these mechanisms is activation and expansion of antigen-specific cytotoxic T cells, after recognition of antigenic peptides on the surface of antigen presenting cells such as dendritic cells (DCs). However, DCs also process and present autoantigens. Therefore, antigen presentation has to occur in the appropriate context to either trigger immune responses or establishing immunological tolerance. This is achieved by co-stimulation of T cells during antigen presentation. Co-stimulation consists on the simultaneous binding of ligand-receptor molecules at the immunological synapse which will determine the type and extent of T cell responses. In addition, the type of cytokines/chemokines present during antigen presentation will influence the polarisation of T cell responses, whether they lead to tolerance, antibody responses or cytotoxicity. In this review, we will focus on approaches manipulating co-stimulation during antigen presentation, and the role of cytokine stimulation on effective T cell responses. More specifically, we will address the experimental strategies to interfere with negative co-stimulation such as that mediated by PD-L1 (Programmed cell death 1 ligand 1)/PD-1 (Programmed death 1) to enhance anti-tumour immunity.

Figure 1. Antigen presentation in the immunological sypnase

The scheme depicts a DC (left) presenting antigen in the context of MHC molecules to a CD4 T cells. The peptide-MHC engages to the T cell TCR delivering signal 1 as shown within the T cells. Simultaneously, co-stimulatory or co-inhibitory ligands on the DC surface (CD80/86, or CD80/PDL1) engage with their receptors on the T cell, leading to either positive stimulation or negative stimulation. The resulting signal from the integration of these co-stimulatory interactions will provide a second signal to T cells. In this scheme, the DC produces cytokines within the immunological synapse, giving a third T cell polarising signal. On the right, the most representative T helper subtypes are shown, and the cytokines promoting these T cell subtypes are also indicated.

Figure 2. Effects of directly or indirectly activated DCs on antigen presentation and T cell polarisation

On top, a directly activated DC through TLR engagement (left) presents antigen to T cells and provide the three activatory signals to the T cells (right). In this case, cytokine priming occurs in cis, leading to T cell proliferation and acquisition of effector activities. On the bottom, an indirectly activated DC through cytokine priming in trans (i.e. cytokines produced by neighbouring cells within an inflammatory environment, left of the scheme). In this situation, cytokines are not produced within the immunological synapse and the resulting T cell proliferates, but does not acquire significant effector activities or a distinct differentiation profile.