Fig. 3.

Factors influencing T cell activation. The formation of the antigenic peptide–MHC-1 complex is a necessary process governing CD8+ T cell activation. Naïve CD8+ T cells may subsequently be activated through their interaction with molecules and cytokines facilitating the activation of their pathways. CD27, CD28, CD69, CD95 and OX40 are costimulatory molecules expressed on CD8+ T cells. The activation of CD8+ T cells is facilitated when any of these costimulatory molecules bind to their respective ligands on APCs. Hypoglycemia and hypoxia lead to increased signaling of peroxisome proliferator-activated receptor (PPAR)-α, facilitating energy generation through fatty acid catabolism and prioritizing CD8+ T cell activation. Th17 cell, a helper T cell, also facilitates CD8+ T cell activation. Naïve CD8+ T cells may be inactivated by the presence of immunosuppressive cells or factors of the TME; interactions with tumor cells; and effects from interactions with other APCs. TAMs secrete TGF-β, IL-10 and ROS to inhibit T cell activation. MDSCs secrete Arg1, iNOS and ROS to inhibit CD8+ T cell activation. Tumor cells expressing PD-L1 or CD80 receptors may bind to corresponding molecules PD-1 and CTLA-4 respectively, causing CD8+ T cell inactivation. Tumor cells may express CD39 and CD73 on their surface facilitating the metabolism of extracellular ATP into AMP and finally into adenosine which inhibits CD8+ T cell activation. Tryptophan is converted into kynurenine through the function of IDO which is produced by the tumor cell. Kynurenine inhibits CD8+ T cell activation. Tumor cells metabolize glucose into lactate and lactate production inhibits CD8+ T cell activation. APCs may express the B7S1 molecule which inhibits CD8+ T cell activation, upon binding to its receptor B7S1R.