T-cell response to checkpoint blockade immunotherapies: from fundamental mechanisms to treatment signatures

Abstract

Immune checkpoint immunotherapies act to block inhibitory receptors on the surface of T cells and other cells of the immune system. This can increase activation of immune cells and promote tumour clearance. Whilst this is very effective in some types of cancer, significant proportions of patients do not respond to single-agent immunotherapy. To improve patient outcomes, we must first mechanistically understand what drives therapy resistance. Many studies have utilised genetic, transcriptional, and histological signatures to find correlates of effective responses to treatment. It is key that we understand pretreatment predictors of response, but also to understand how the immune system becomes treatment resistant during therapy. Here, we review our understanding of the T-cell signatures that are critical for response, how these immune signatures change during treatment, and how this information can be used to rationally design therapeutic strategies. We highlight how chronic antigen recognition drives heterogeneous T-cell exhaustion and the role of T-cell receptor (TCR) signal strength in exhausted T-cell differentiation and molecular response to therapy. We explore how dynamic changes in negative feedback pathways can promote resistance to single-agent therapy. We speculate that this resistance may be circumvented in the future through identifying the most effective combinations of immunotherapies to promote sustained and durable antitumour responses.

Keywords: Anti-tumour immune responses; Immunotherapy; T cell exhaustion; T cell receptor signalling; T cells.

Figure 1. Graphical representation of reported changes to function of CD4⁺ T cells, CD8⁺ T cells, and DCs in response to αPD-L1 immunotherapy

Distinct from direct effect on CD8⁺ T cells, immunotherapy can act via CD4⁺ T cells and DCs to support CD8⁺ T-cell function via cytokine production and costimulation.

Figure 2. Graphical representation showing how αPD-L1 immunotherapy can modulate intratumoural CD8⁺ T-cell differentiation during treatment

Ineffective response may be a result of poor pre-existing response or previous terminal differentiation. Presence of less-differentiated T_PEX cells allows for proliferative burst and differentiation, driving clinical benefit.