Focus on T cell exhaustion: new advances in traditional Chinese medicine in infection and cancer

Abstract

In chronic infections and cancers, T lymphocytes (T cells) are exposed to persistent antigen or inflammatory signals. The condition is often associated with a decline in T-cell function: a state called "exhaustion". T cell exhaustion is a state of T cell dysfunction characterized by increased expression of a series of inhibitory receptors (IRs), decreased effector function, and decreased cytokine secretion, accompanied by transcriptional and epigenetic changes and metabolic defects. The rise of immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has dramatically changed the clinical treatment paradigm for patients. However, its low response rate, single target and high immunotoxicity limit its clinical application. The multiple immunomodulatory potential of traditional Chinese medicine (TCM) provides a new direction for improving the treatment of T cell exhaustion. Here, we review recent advances that have provided a clearer molecular understanding of T cell exhaustion, revealing the characteristics and causes of T cell exhaustion in persistent infections and cancers. In addition, this paper summarizes recent advances in improving T cell exhaustion in infectious diseases and cancer with the aim of providing a comprehensive and valuable source of information on TCM as an experimental study and their role in collaboration with ICIs therapy.

Keywords: Cancer; Immune checkpoint inhibitors; Infection; T cell exhaustion; Traditional Chinese medicine.

Fig. 1

Inhibitory receptors associated with T cell exhaustion and related ligands. APC antigen-presenting cell, PD-1 programmed cell death protein 1, PD-L1 programmed cell death 1 ligand 1, PD-L2 programmed cell death 1 ligand 2, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, TIM-3 T cell immunoglobulin domain and mucin domain protein 3, Gal-9 Galectin-9, CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1, HMGB-1 high-mobility

Fig. 2

Interaction and functions of immune cells in tumor microenvironment. Cancer cells, Tregs, NK, TAM, MDSC and CD4 T cells are important immune cells that regulate CD8 T-cell exhaustion. IL-2, IL-6, IL-10, IL12, TGF-β, TNF-α and IFN-γ are all important exogenous cytokines involved in exhausted process of T cells. TAM tumor-associated macrophage, Treg regulatory cells, NK natural killer cell, MDSC myeloid-derived suppressor cells

Fig. 3

Blockade of CTLA-4, or PD-1, or PD-L1 signaling in tumor immunotherapy. The activation of T cells requires double signaling. The first signal of T cell activation comes from the specific binding of TCR to MHC. The second signal of T cell activation comes from costimulatory molecules, namely signals mediated by the interaction of APC-expressed costimulatory molecules with corresponding receptors or ligands on the T cell surface. Costimulatory molecules can be divided into positive co-stimulatory molecules and negative co-stimulatory molecules. CD28/B7 is an important positive co-stimulatory molecule, and CTLA-4, which is highly homologous to CD28 molecule, has a ligand of B7, but the binding of CTLA-4 and B7 mediates the conduction of negative signals. Anti-CTLA-4 maintains T cell activation by blocking the transmission of inhibitory signals by inhibiting the binding of CTLA-4 to CD80 or CD86 molecules. When T cells kill tumor cells, the combination of PD-L1 expressed on tumor cells and PD-1 expressed on T cells will transmit negative regulatory signals to T cells, causing T cells to be unable to recognize cancer cells and tumor cells to achieve “immune escape”. Anti-PD-1 or anti-PD-L1 prevents PD-L1 from binding to PD-1, thereby reactivating T cells to kill tumors