Fig. 2

Cancer-immunity cycle and T-cell exhaustion in the tumor ecosystem. a Cancer-immunity cycle. Cancer antigens that are derived from destroyed cancer cells are engulfed and presented on the surface of antigen presenting cells (APCs), followed by the priming and activation of T-cells and APCs specific for cancer antigens. Upon activation of effector T-cells or APCs, the effector T-cells bearing cancer antigen-specific TCRs traffic and infiltrate into the tumor sites, recognize cancer cells with the expression of these antigens, and mediate the targeted-killing of cancer cells, which can be processed and presented by APCs in turn. b T-cell exhaustion in the tumor ecosystem. T-cell exhaustion refers to the dysfunctional and hypo-responsive state of T-cells, characterized by reduced proliferation and cytokine production, as well as impaired cytotoxicity due to decreased expression of granzyme B. Memory and effector T-cells can differentiate into exhausted T-cells in the tumor ecosystem consisting of tumor clones, stromal cells and immune cells, which can provide internal and external signals for T-cell exhaustion. The internal signals of T-cells in exhaustion are attributed to the enhanced expression of inhibitory receptors (for example, PD-1, CTLA-4, TIM-3, LAG-3, BTLA and TIGIT), the decreased release of immunostimulatory cytokines (IL-2, TNF-α, IFN-γ) and the transactivation of transcription factors (T-bet^−/+, NFAT, Blimp-1). External signals of exhausted T-cells are from soluble factors (TGF-β, IL-10), stromal cells that can secrete cytokines, immunosuppressive cells (eg. Macrophages and dendritic cells) and deregulated metabolism in the tumor ecosystem. Early exhausted T-cells can be reversed to effector T-cells with treatment of anti-PD-1/PD-L1. TIM-3: T cell immunoglobulin and mucin domain containing-3; BTLA: B and T lymphocyte attenuator; TIGIT: T cell immunoreceptor with Ig and ITIM domains; NFAT: nuclear factor of activated T cell; Blimp-1: B lymphocyte-induced maturation protein 1