T-cell exhaustion in the tumor microenvironment

Abstract

T-cell exhaustion was originally identified during chronic infection in mice, and was subsequently observed in humans with cancer. The exhausted T cells in the tumor microenvironment show overexpressed inhibitory receptors, decreased effector cytokine production and cytolytic activity, leading to the failure of cancer elimination. Restoring exhausted T cells represents an inspiring strategy for cancer treatment, which has yielded promising results and become a significant breakthrough in the cancer immunotherapy. In this review, we overview the updated understanding on the exhausted T cells in cancer and their potential regulatory mechanisms and discuss current therapeutic interventions targeting exhausted T cells in clinical trials.

Figure 1

T-cell exhaustion and differentiation in TME. Naive T cells (CD44^lowCD62L^hi) activate and differentiate into effector T cells (CD44^hiCD62L^low) in secondary lymphoid organ. When effector T cells enter TME, they are polarized into exhausted T cells, with decrease in effector cytokines (IL-2/IFN-γ/TNF-α/GzmB) and increase in inhibitory receptors (PD-1/CTLA-4/TIM-3/LAG-3//BTLA/TIGIT). Subsequently exhausted T cells may turn to be defective memory T cells or be deleted physically

Figure 2

Potential regulatory mechanisms of T-cell exhaustion in TME. Cancer cells and stromal cells (tumor-associated DC, Treg, TAM and MDSC) are major extrinsic cells that regulate T-cell exhaustion, and IL-10 and TGF-β are both important extrinsic cytokines involved in exhausted process of T cells. Inhibitory receptors PD-1, CTLA-4, Tim-3, BTLA, LAG-3 and TIGIT on T cells are the major intrinsic regulatory factors of T-cell exhaustion. SHP-2 is the downstream of PD-1, IRF-9 and AP-1, which regulate PD-1 expression in transcriptional level