Legends to Figures
Figure 1: Emerging Immune Checkpoints in cancer immunotherapy: Interaction of emerging immune checkpoint receptors and their respective ligands. Various immune checkpoint molecules expressed on T cells are shown with their ligands on Antigen presenting cells or tumor cells. A.  TIGIT and CD226 bind to the same ligands, CD112 and CD155. CD226 is a co-stimulatory receptor whereas TIGIT is a co-inhibitory receptor. TIGIT binds with CD112/CD155 with higher affinity than CD226 leading to the suppression of T cell and natural killer (NK) cell activity, thereby contributing to immune evasion by tumors. B. LAG3 binds to MHC-II to inhibit CD4-dependent T cell function with its cytoplasmic domain. TME-derived Galectin3 and LSECtin bind with LAG3 to inhibit T cell function, which requires the KIEELE motif in the LAG3 cytoplasmic domain. C. B7 family receptors (B7-H3, B7- H4, HHLA2) and their known and unknown ligands are inhibitory molecules which mediate various mechanisms to evade tumour-antigen-specific T-cell immunity, including T-cell apoptosis, anergy and exhaustion. D. TIM-3 is expressed in both T cells and innate immune cells, with four known ligands including Ceacam1, Galectin-9, HMBG1, and PS. In the absence of ligands, Bat3 binds to unphosphorylated TY256/263 in TIM3 cytoplasmic domain and recruits active Lck to deliver stimulatory signal in T cells. Interaction with Galectin9/Ceacam1 leads to phosphorylation of TIM3 TY256/263 and the subsequent abolishment of Bat3 binding. Thus, functioning as an inhibitory receptor and contributing to immune tolerance and anti-tumor immunity suppression. E. CD47 interacts with SIRPα, acting as a "don't eat me" signal to prevent macrophages and phagocytes from engulfing cancer cells. Siglec-15 interacts with sialylated ligands, modulating immune responses in the tumor microenvironment and contributing to immune evasion. F. VISTA serves dual immunosuppressive roles as both a ligand on tumor cells/APCs with PSGL-1 being its receptor on T cells and a receptor on T cells with VSIG-3 as its ligand. G. BTLA interacts with HVEM on APC/tumor cells causing NF-kb activation. ITIM and ITSM in BTLA recruit SHP1/SHP2 to inhibit both TCR and CD28 signaling.
BTLA (B- and T-lymphocyte attenuator); HMGB1 (High mobility group box 1); ITIM (immunoreceptor tyrosine-based inhibitory motif); LAG3 (Lymphocyte Activation Gene 3); ITSM (immunoreceptor tyrosine-based switch motif); PSGL-1 (P-selectin glycoprotein ligand-1); SIRPα (Signal regulatory protein ALPHA); TIGIT (T cell immunoreceptor with immunoglobulin and ITIM domain); SHP2 (Src-homology-2-containing Protein tyrosine phosphatases-2); Tim-3 (T-cell immunoglobulin and mucin domain 3); TME (tumor microenvironment); VISTA (V-domain immunoglobulin suppressor of T-cell activation)
Figure 2: Novel Co-stimulatory molecules: This diagram illustrates the interaction of various novel costimulatory molecules on T cells with their corresponding ligands on antigen-presenting cells (APCs), highlighting their roles in T cell activation and immune response modulation. GITR (Glucocorticoid-Induced TNFR-related protein), ICOS (Inducible T cell Co-Stimulator), DR3 (Death Receptor 3), TCR (T Cell Receptor), MHC (Major Histocompatibility Complex).
Figure 3: Targeting the Tumor Microenvironment: This diagram illustrates key pathways and targets within the tumor microenvironment. The adenosine pathway includes CD39 and CD73, which convert ATP to adenosine, leading to immunosuppression. TAM receptors (Tyro3, Axl, Mer) are shown, which mediate immune evasion and tumor progression. Neoantigens and TCR engineering are highlighted, representing the identification of tumor-specific antigens and the modification of T cells to enhance anti-tumor immune responses.