Overcoming T cell exhaustion in infection and cancer

Abstract

Inhibitors of the Programmed Cell Death 1: Programmed Cell Death 1 ligand 1 (PD-1:PD-L1) pathway, a central regulator of T cell exhaustion, have been recently shown to be effective for treatment of different cancers. However, clinical responses are mixed, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. Here, we review the molecular regulation of T cell exhaustion, placing recent findings on PD-1 blockade therapies in cancer in the context of the broader understanding of the roles of the PD-1:PD-L1 pathway in T cell exhaustion during chronic infection. We discuss the current understanding of the mechanisms involved in reversing T cell exhaustion, and outline critical areas of focus for future research, both basic and clinical.

Keywords: PD-1; PD-L1; T cell exhaustion; cancer; chronic infection; immunotherapy.

Figure 1. Development and functions of CD8⁺ T cells responding during acute versus chronic antigen encounter

(A) Dynamics of CD8⁺ T cell expansion, contraction, and memory formation following acutely resolved antigen stimulation. Following activation, naïve T cells convert into an effector population consisting of KLRG1^hi CD127^lo short-lived effector cells and KLRG1^lo CD127^hi memory precursor cells. Following antigen clearance, memory T cell populations form predominantly from KLRG1^lo CD127^hi precursor cells. Memory CD8⁺ T cells retain the ability to re-expand upon secondary antigen encounter, resulting in an anamnestic response that controls antigen more rapidly than during the primary response [61]. (B) Dynamics of CD8⁺ T cell populations during chronic antigen encounter. Following activation, naïve T cells differentiate into an effector T cell population similarly to that observed following acutely resolved antigen encounter (A). However, the failure to eliminate antigen leads to the progressive development of exhaustion. T_EX arise from the KLRG1^lo CD127^hi subset, a shared feature with memory T cells (A) [55]. These T_EX exert pressure on the pathogen or tumor, resulting in a host-pathogen or host-tumor stalemate. Following intervention with immunotherapy including PD-1 pathway blockade, T_EX can be reinvigorated, restoring effector functions and increasing cell numbers, resulting in decreased antigen load. However, the durability of this enhancement in the CD8⁺ T cell response is currently unknown. In (A) and (B), red lines indicate antigen-specific CD8⁺ T cell magnitude, grey lines indicate antigen level. (C) Comparison of key properties of memory, exhausted, and anti-PD-1:PD-L1-treated “reinvigorated” CD8⁺ T cells populations [3].

Figure 2. Heterogeneity in the T_EX population

During chronic infection, two subsets of CD8⁺ T cells have been identified based on expression of PD-1 and the T-box transcription factors T-bet and Eomes [35]. Cells that express high levels of T-bet, lower levels of Eomes, and intermediate levels of PD-1 retain greater proliferative potential, the ability to produce slightly greater amounts of IFNγ and TNFα, are preferentially found in the spleen and blood [35], and are more responsive to reinvigoration following PD-1 pathway blockade [59]. Cells that express higher Eomes, lower T-bet, and high PD-1 show elevated expression of other inhibitory receptors (IRs) (e.g. Tim-3, CD160, and Lag-3), reduced proliferative potential and reduced co-production of IFNγ and TNFα, but retain a greater capacity for killing and preferentially localize to non-lymphoid tissues [35]. These cells also display reduced potential for reinvigoration by PD-1 pathway blockade [59]. Importantly, there is a lineage relationship between these two subsets. The T-bet^Hi PD-1^int subset serves as a progenitor population for both maintaining itself and the Eomes^Hi PD-1^Hi terminal-progeny subset [35]. The conversion from T-bet^Hi PD-1^int to Eomes^Hi PD-1^Hi cells is linked to extensive antigen-driven proliferation. High levels of antigen and/or lack of CD4⁺ T cell help favor the conversion from T-bet^Hi to Eomes^Hi cells [35].

Figure I. Mechanisms of PD-1-mediated inhibition in T cells

Five main mechanisms have been proposed for how PD-1 modulates T cell functions. PD-1 can: (A) directly antagonize T cell receptor (TCR) signaling by recruiting phosphatases to tyrosine-containing motifs in the PD-1 tail [108], which can prevent LCK-mediated phosphorylation of ZAP70 [110], (B) inhibit CD28-induced activation of PI3K, leading to reduced AKT and mTOR activation [111], (C) inhibit the Ras pathway [112], (D) induce increased expression of transcription factors including BATF, which can directly suppress transcription of various effector genes [113], and (E) impact T cell motility and the stability/duration of T cell/APC interactions [–116].