T Cell Dysfunction in Cancer

Abstract

Therapeutic reinvigoration of tumor-specific T cells has greatly improved clinical outcome in cancer. Nevertheless, many patients still do not achieve durable benefit. Recent evidence from studies in murine and human cancer suggest that intratumoral T cells display a broad spectrum of (dys-)functional states, shaped by the multifaceted suppressive signals that occur within the tumor microenvironment. Here we discuss the current understanding of T cell dysfunction in cancer, the value of novel technologies to dissect such dysfunction at the single cell level, and how our emerging understanding of T cell dysfunction may be utilized to develop personalized strategies to restore antitumor immunity.

Keywords: PD-1; T cell exhaustion; cancer; cancer immunotherapy; single cell technologies; tumor microenvironment.

Figure 1. Drivers of T Cell Dysfunction in Cancer

Dysfunctional T cells in cancer share core exhaustion features with dysfunctional T cells in chronic infection that are at least partially driven by chronic TCR stimulation. The consequences of chronic TCR signaling are further modulated by a multitude of immunosuppressive signals in the TME, including inhibitory ligands, suppressive soluble mediators, cell subsets, and metabolic factors. Strength of these different signals is determined by parameters such as the specific mutations in the cancer cells, spatial gradients in tumor composition, and therapy-induced alterations in the TME. Collectively, the immunosuppressive signals in the TME shape the (dys-)functional state of intratumoral T cells by influencing the expression of inhibitory receptors, changing metabolic pathways, modifying the epigenetic state, and altering their transcription factor profiles.

Figure 2. Comparison of Single Cell Technologies to Dissect Intratumoral T Cell Dysfunction

Technologies that assess T cell dysfunction at the single cell level are required to describe the heterogeneity of functional states within the TME. Current single cell technologies differ in the complexity and spatial resolution they provide. Ability to provide multiparameteric information with respect to RNA and protein expression, and ability to provide spatial information are depicted for the indicated technologies. Asterisks indicate technologies that also provide TCR sequence information and may be combined with functional testing to evaluate tumor reactivity.