Immune Recognition of Tumour Antigens by T Cells
During the priming phase of anti-tumour immunity, tumour antigens are presented to T cells via APCs, such as dendritic cells (DCs) or macrophages. The specificity of T cell activation against a tumour antigen relies on the cognate recognition of the antigen presented by the major histocompatibility complex (MHC) proteins on the surface of APCs and the T cell receptor (TCR). During the effector phase of the anti-tumour immune response, primed T cells will recognise the tumour antigens presented by MHC molecules expressed by the tumour cells. CD8+ and CD4+ T cells can recognise peptides presented by MHC-I and MHC-II molecules, respectively. This TCR/MHC interaction provides the first signal for T cell activation (signal 1).
The activation of a T cell also requires a second signal, provided by co-stimulatory molecules. The first co-stimulatory molecules historically identified belong to the immunoglobulin B7 superfamily. CD80 (also known as B7.1) and CD86 (also known as B7.2) are expressed at the surface of either APCs or cancer cells, and act as activating ligands of the co-stimulatory receptor CD28 expressed on the surface of T cells (signal 2). More recently, other co-stimulatory immune checkpoints have been described, such as OX40 (CD134), 4-1BB (CD137) or GITR (CD357). These TCRs belong to the TNF superfamily receptors (TNFSFRs) and their activation enhances T cell survival and effector functions. From the same family, CD40 is expressed on APCs and amplifies T cell activation by increasing antigen presentations. Interestingly, co-stimulatory molecules are also highly expressed on immunosuppressive regulatory T cells (Tregs). The activation of Tregs favours immune self-tolerance. Defective Tregs have been associated with autoimmune disorders, while intratumoural Tregs have been associated with a worse prognosis in many cancers.
Upon T cell activation, negative feedback loops can prevent overstimulation of self-reactivity. Like the CD28 receptor structure, but with opposite effects, the co-inhibitory receptor CTLA-4 has been shown to bind to CD80 and CD86 with a much higher affinity than CD28, delivering inhibitory signals to T cells and therefore blocking T cell activation. The membrane expression of CTLA-4 is mostly found on CD4+ T cells, notably Tregs (Figure 1). Upon activation, the PD-1 receptor can be upregulated on T cells and can interact with two ligands: programmed death-ligand 1 (PD-L1) (also known as B7H1 or CD274) and PD-L2 (also known as B7DC or CD273). Once bound to its ligands, PD-1 confers a negative signal to effector T cells, thereby inhibiting their cytotoxic functions. CTLA-4 and PD-1 are usually highly expressed on intratumoural T cells and their stimulation is thought to contribute to the overall inhibition of anti-tumour T cells.
Figure 1: Evolution of CTLA-4 and PD-1 immune checkpoint expression in the immune response
Immune Checkpoint-targeted Therapies
The scientific rationale that anti-tumour T cells could be blocked in their functions by co-inhibitory receptors led to the idea of designing antagonistic antibodies to dampen the CTLA-4/B7 and PD-1/PD-L1/2 interactions, and unleash the effector signals on T cells either at the priming or effector phases. This idea has been a major paradigm shift in the strategy to treat cancers, where instead of designing tumour-targeted therapies, we would now design immune-targeted therapies in order to break the cancer immune tolerance, restoring T cell recognition against tumour cells.