CD8+ T cells in the cancer-immunity cycle

Abstract

CD8⁺ T cells are end effectors of cancer immunity. Most forms of effective cancer immunotherapy involve CD8⁺ T cell effector function. Here, we review the current understanding of T cell function in cancer, focusing on key CD8⁺ T cell subtypes and states. We discuss factors that influence CD8⁺ T cell differentiation and function in cancer through a framework that incorporates the classic three-signal model and a fourth signal-metabolism-and also consider the impact of the tumor microenvironment from a T cell perspective. We argue for the notion of immunotherapies as "pro-drugs" that act to augment or modulate T cells, which ultimately serve as the drug in vivo, and for the importance of overall immune health in cancer treatment and prevention. The progress in understanding T cell function in cancer has and will continue to improve harnessing of the immune system across broader tumor types to benefit more patients.

Keywords: CD8 T cells; T cell exhaustion; cancer; immune checkpoint blockade; immunology; immunotherapy; metabolism.

Figure 1:. CD8⁺ T cell differentiation: Two pathways

A. Upon activation, naïve CD8⁺ T cells differentiate down two main developmental pathways which are regulated, in part, by four signals. B. Conventional classification scheme for human memory CD8⁺ T cells. Below each subset are expression profiles commonly used for identifying these subsets within Tmem population. Key functional characteristics are depicted by relative expression across the memory CD8⁺ T cell differentiation spectrum. These comparisons focus on later stage memory fate-committed subsets. C. The three major Texh subtypes with expression profiles commonly used for identification within Texh population. The relative expression of various traits, functions, and expression profiles across subsets within Texh population are represented below. These comparisons focus on later stage exhaustion fate-committed subsets.

Figure 2:. Four signal model of T cell activation and differentiation

Signal 1 is TCR recognition of peptides presented on MHC molecules. In cancer, these antigens are classified as tumor-associated antigen (TAAs) which can be expressed by both tumor and healthy tissue or tumor-specific antigens (TSAs) which are exclusively expressed by cancer cells. Signal 2 encompasses co-stimulatory and co-inhibitory signals, the balance of which influences T cell activation status and effector functions. Signal 3 includes signaling received through cytokines. The 3 main classes of cytokines include inflammatory, growth/survival, and regulatory. Signal 4 includes nutrient sensing and usage as well as internal changes in metabolic lifestyle.

Figure 3:. Metabolic ecosystems in the TME

The metabolic states of different cell types and their fuel preferences, as well as histological landmarks in the tumor microenvironment (TME) such as vasculature can create metabolic niches. These niches in combination with the cellular interactions of T cells with other immune and non-immune cell types generate immunosupportive (green) or immunosuppressive (red) conditions, that can influence T cell differentiation and function. Progenitor exhausted and more terminal exhausted T cells display unique metabolic characteristics.

Figure 4:. The immune system is the active drug component of immunotherapy

A. Immunotherapies, such as ICB, represent pro-drugs that are taken by patients. These pro-drugs (i.e. αPD-1) act on cells in the endogenous immune system, such as ineffective Texh cells. These modified endogenous cells (such as “reinvigorated” Texh cells) then represent the active drug which mediates the anti-tumor activity. In this scenario, traditional pharmacology concepts such pharmacokinetic/pharmacodynamic (PK/PD) measurements and modeling can be applied to the active drug, the modified immune cells, instead of the pro-drug. In this case, the kinetics, magnitude, and duration of the T cell response would be treated as the measurements of interest. B. Cellular therapy, such as CAR T cells, or other engineered cells including TIL, are manufactured from a pro-drug (ineffective and unmanipulated endogenous CD8⁺ T cells) to an active drug in vitro (i.e. CART19) which are then transferred in vivo to mediate tumor killing.