Biomarkers of response to PD-1 pathway blockade

Abstract

The binding of T cell immune checkpoint proteins programmed death 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to their ligands allows immune evasion by tumours. The development of therapeutic antibodies, termed checkpoint inhibitors, that bind these molecules or their ligands, has provided a means to release this brake on the host anti-tumour immune response. However, these drugs are costly, are associated with potentially severe side effects, and only benefit a small subset of patients. It is therefore important to identify biomarkers that discriminate between responders and non-responders. This review discusses the determinants for a successful response to antibodies that bind PD-1 or its ligand PD-L1, dividing them into markers found in the tumour biopsy and those in non-tumour samples. It provides an update on the established predictive biomarkers (tumour PD-L1 expression, tumour mismatch repair deficiency and tumour mutational burden) and assesses the evidence for new potential biomarkers.

Fig. 1. Physiological role of PD-L1.

a Most T cells are unable to recognise self-antigens, which may be present on the surface of self-cells or APCs. As a result, there is no autoimmunity. b Autoreactive T cells can recognise self-antigens and become activated, leading to destruction of the self-cell. c PD-L1 expression on self-cells and APCs prevents T cell activation, despite TCR ligation. APC antigen-presenting cell, TCR T cell receptor, MHC major histocompatibility complex.

Fig. 2. Mechanism of action of anti-PD-1 and anti-PD-L1 antibodies.

a In a PD-L1 negative tumour, tumour neoantigens presented on the surface of tumour cells or APCs are detected by T cells, which are then activated to destroy the tumour cell. b Tumour cell or APC expression of PD-L1 prevents T cell activation and allows immune evasion. c Anti-PD-I antibodies can bind to PD-1 on T cells, preventing the interaction between PD-1 and PD-L1 and therefore enabling tumour cell destruction. d Anti-PD-L1 antibodies can bind to PD-L1 on tumour cells and APCs, preventing the interaction between PD-1 and PD-L1 and enabling tumour cell destruction.

Fig. 3. Grouping of biomarkers.

Biomarkers are grouped depending on whether they are found in the tumour biopsy or non-tumour samples. Those found in the tumour biopsy are further subdivided into those obtained through genetic tests and non-genetic other tests. TMB tumour mutational burden, MMR mismatch repair, MHC-I major histocompatibility complex class I, TME tumour microenvironment, TII tumour infiltrating immune cells.