Fig. 2

Antagonistic and agonistic antibodies act on inhibitory immune checkpoints and co-stimulatory molecules respectively to promote anti-tumoral T cell functions. By blocking the inhibitory receptor-ligand binding process, antagonistic antibodies prevent the activation of inhibitory downstream signaling in T cells, thereby sustaining the function, proliferation, and survival of T cells (left panel). Beyond the two first confirmed receptor-ligand pairs, PD-1-PD-L1 and CTLA-4-CD80/CD86, more and more immune checkpoint receptor-ligand pairs have been identified. Besides the interaction between specific cognate receptor and ligand pairs, inter-relationships exist between certain immune checkpoints such as PD-1 and TIGIT/CD226. With a certain amount of redundancy and robustness, these inhibitory circuits guarantee balanced T cell immunity under physiological conditions. However, these mechanisms are utilized by cancer cells and the inhibitory TME to limit anti-tumor immunity. By promoting trimerization and superclustering, agonistic antibodies promote and amplify downstream signaling of co-stimulatory molecules to sustain the function, proliferation, and survival of T cells (right panel). Likewise, by upregulating the expression of receptors and ligands, inter-relationships also exist between co-stimulatory molecules such as CD28 and CD40. Another strategy using agonistic antibodies is modifying the Fc segment to predispose agonists to bind activating FcγRs for Treg depletion. DC Dendritic cell, cGAS-STING cyclic GMP-AMP synthase-stimulator of interferon genes, pMHCII peptide major histocompatibility complex class II, PD-1 programmed cell death protein 1, PD-L1 programmed death-ligand 1, FGL1 fibrinogen-like protein 1, HMGB1 high mobility group box 1, CTLA-4 cytotoxic T-lymphocyte-associated protein 4, LAG-3 lymphocyte-activation gene 3, TIM-3 T-cell immunoglobulin and mucin-domain containing-3, CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1, KIR2DL5 killer cell immunoglobulin-like receptor, two Ig domains and long cytoplasmic tail 5, Eomes eomesodermin, TIGIT T-cell immunoreceptor with Ig and ITIM domains, PtSer phosphatidylserine, TLT-2 triggering receptor expressed on myeloid cells 2, PSGL-1 P-selectin glycoprotein ligand-1, SIRPα signaling-regulatory protein α, APC antigen-presenting cell, NF-κB nuclear factor kappa B, ICOS inducible T-cell costimulator, ICOSL inducible T-cell costimulator ligand, FcγR Fc gamma receptor, Treg regulatory T cell