Establishing a human in vitro model of T cell exhaustion

Abstract

Reviving the activity of tumor-specific T lymphocytes has improved cancer treatment since the introduction of immunotherapy, specifically immune checkpoint inhibition. Nevertheless, a large number of individuals do not respond or have a long-lasting response. Tumor infiltrating T cells indeed can exhibit a wide range of dysfunctional states, referred to as exhaustion. This exhausted state is thought to be an important contributor in non-response to immune checkpoint inhibition. On top of chronic antigen stimulation, many suppressive elements present in the tumor microenvironment influence T cell progression to exhausted states. Studies in murine systems and on human tumor samples have thus far brought insight into the mechanisms inducing- and influencing progression of exhaustion in the T cells. In this study, we present a provisional human model for in vitro T cell exhaustion. In this model, we show upon activation with T cell receptor stimulating beads that CD8+ T cells express hallmark surface receptor PD-1 and key transcription factor TOX. Additionally, both CD4+ and CD8+ T cells express other inhibitory receptors. Furthermore, expression of Eomes is revoked upon stimulation, indicating that the T cells display intermediate substages of exhaustion. Taken together, T cell receptor stimulation with beads can partially mimic T cell exhaustion in a model which can be used and optimized to further investigate effects of the tumor microenvironment on T cell activation and exhaustion, and how this may be contributing to immunotherapy response.