T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment

Abstract

Human tumors progress despite the presence of tumor associated antigen (TAA)-specific T cells. Many different molecular and cellular mechanisms contribute to the failure of T cells to eradicate the tumor. These include immune suppressive networks that impair ongoing T cell function and enable tumor escape. Recent studies have started to reveal the nature of effector T cells in the tumor microenvironment. In this article we discuss T cell anergy, exhaustion, senescence, and stemness, and review the phenotype of dysfunctional T cell subsets and the underlying molecular mechanisms in the tumor microenvironments. We suggest that targeting T cell dysfunctional mechanisms and introducing/promoting T cell stemness are important approaches to treat patients with cancer.

Figure 1. General characteristics for anergic, exhausted, senescent and stem-like T cells

a) Anergic T cells are T cells stimulated with low co-stimulatory and/or high co-inhibitory signaling. These cells are unresponsive to subsequent activating conditions with limited IL-2 expression. (b) Exhausted T cells are effector T cells that have lost their effector functions including effector cytokine expression due to repeated stimulation. These cells express multiple regulatory receptors. (c) Senescent T cells are described as unresponsive/terminally differentiated T cells. The hallmark is their cell cycle arrest along with limited CD28 expression and/or high levels of regulatory receptor expression. (d) Stem-like T cells may show a naïve or memory phenotype. Importantly, these cells are capable of self-renewal, have enhanced anti-tumor responses and are long-lived effector cells.

Figure 2. Immunoregulatory receptors and their ligands

T cell activation relies on the T cell receptor (TCR) recognizing its cognate antigen in the context of MHC molecules from an antigen presenting cell (APC) or an APC-like cell (tumor cell). Interaction between co-stimulatory molecules CD80, and CD86 and CD28 is crucial for appropriate T cell activation. Immunoregulatory receptors such as CTLA-4 and PD-1 are to fine tune T cell activation. High levels of multiple immunoregulatory receptors (LAG-3, 2B4, CD160, KLRG1, Tim-3, CTLA-4, and CD57) or their ligands are found in the tumor microenvironment. Potent and lasting immunoregulatory signaling results in reduced T cell function and tolerance.