Clinical implications of T cell exhaustion for cancer immunotherapy

Abstract

Immunotherapy has been a remarkable clinical advancement in the treatment of cancer. T cells are pivotal to the efficacy of current cancer immunotherapies, including immune-checkpoint inhibitors and adoptive cell therapies. However, cancer is associated with T cell exhaustion, a hypofunctional state characterized by progressive loss of T cell effector functions and self-renewal capacity. The 'un-exhausting' of T cells in the tumour microenvironment is commonly regarded as a key mechanism of action for immune-checkpoint inhibitors, and T cell exhaustion is considered a pathway of resistance for cellular immunotherapies. Several elegant studies have provided important insights into the transcriptional and epigenetic programmes that govern T cell exhaustion. In this Review, we highlight recent discoveries related to the immunobiology of T cell exhaustion that offer a more nuanced perspective beyond this hypofunctional state being entirely undesirable. We review evidence that T cell exhaustion might be as much a reflection as it is the cause of poor tumour control. Furthermore, we hypothesize that, in certain contexts of chronic antigen stimulation, interruption of the exhaustion programme might impair T cell persistence. Therefore, the prioritization of interventions that mitigate the development of T cell exhaustion, including orthogonal cytoreduction therapies and novel cellular engineering strategies, might ultimately confer superior clinical outcomes and the greatest advances in cancer immunotherapy.

Fig. 1 |. Tumour-reactive CD8⁺ T cells undergo progressive exhaustion in the TME.

a | Naive CD8⁺ T cells (T_n) can differentiate along of spectrum of exhaustion states associated with progressively declining functional and proliferative capacity, spanning from stem-like precursor exhausted T cells (T_PEX) to terminally exhausted T cells (T_EX) that can ultimately undergo overstimulation-induced cell death. In the setting of persistent exposure to tumour antigen, expression of the transcription factor TCF1 in the T cell decreases while expression of TOX family transcription factors increases. As a result, expression of exhaustion markers (such PD-1, TIM-3, LAG-3 and CD39) will increase, effector function will decrease and the T cell will incur metabolic dysfunction. However, the tempo at which an individual T cell becomes exhausted is context-dependent (as indicated in the top right of the figure); the various T cell-intrinsic and T cell-extrinsic factors that modulate this process include the antigenic load, tissue oxygen concentration, immune contexture and target cell sensitivity to T cell-mediated cytotoxicity. b |Although the key mechanism of anti-PD-(L)1 antibody therapy was initially believed to be functional reinvigoration of exhausted T cells in the tumour microenvironment (TME), more recent data indicates that abrogation of the priming interaction between dendritic cells and precursor exhausted CD8⁺ T cells in tumour-draining lymph nodes is the crucial mechanistic target of such immune-checkpoint inhibitors.

Fig. 2 |. Overview of strategies to mitigate or interrupt CAR T cell exhaustion.

Downstream signalling induced by the chimeric antigen receptor (CAR) activates the transcription factor NFAT. Chronic NFAT signalling leads to expression of NR4A and TOX family transcription factors, which are crucial mediators of the epigenetic and transcriptional programme of T cell exhaustion. Cooperation between NR4A and TOX transcription factors results in the expression of genes encoding co-inhibitory receptors, such as PD-1, and also results in reduced cytokine production and effector function (not shown). Potential interventions to improve the function and thus therapeutic efficacy of CAR T cells are indicated in text boxes and are categorized as strategies that either mitigate T cell exhaustion (a) or more directly interrupt the exhaustion cascade downstream of NFAT signalling (b). a | Interventions to optimize effector-to-target ratios in the patient undergoing CAR T cell therapy, culture conditions during CAR T cell manufacturing, CAR signalling, transcriptional and/or epigenetic programmes and mitochondrial fitness might mitigate T cell exhaustion. b |More downstream interventions targeting the canonical transcription factors associated with T cell exhaustion (that is, NR4A and TOX) and co-inhibitory receptors are strategies to interrupt T cell exhaustion. DNR, dominant-negative receptor; ICIs, immune-checkpoint inhibitors; NAC, N-acetylcysteine; ROS, reactive oxygen species.