Abstract
BackgroundTIGIT, as a novel immune checkpoint molecule involved in T cell and NK cell anergy, could induce the immune tolerance and escape through binding with its ligand PVR. Blockade of TIGIT/PVR is considered as a promising strategy in cancer immunotherapy. However, to facilitate the design of inhibitors targeting TIGIT/PVR, the structural characteristics and binding mechanism still need to be further studied.MethodsIn this study, molecular dynamics (MD) simulations and in silico mutagenesis were used to analyze the interaction between TIGIT and its ligand PVR. Then, PVR mutants were designed and their activities were determined by using TIGIT overexpressed Jurkat cells.ResultsThe results suggested that the loops of PVR (CC′ loop, C′C″ loop, and FG loop) underwent a large intra-molecular rearrangement, and more hydrogen bond crosslinking between PVR and TIGIT were formed during MD simulations. The potential residues for PVR to interact with TIGIT were identified and utilized to predict high affinity PVR mutants. Through the biological activity evaluation, four PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) with enhanced affinity to TIGIT were discovered, which could elicit more potent inhibitory effects compared with the wild type PVR.ConclusionsThe MD simulations analysis provided new insights into the TIGIT/PVR interaction model, and the identified PVR mutants (PVRS72W, PVRS72R, PVRG131V and PVRS132Q) could serve as new candidates for immunotherapy to block TIGIT/PVR.2d6XcvYmuyXjE1VVjjMoDLVideo
Highlights
TIGIT, as a novel immune checkpoint molecule involved in T cell and natural killer (NK) cell anergy, could induce the immune tolerance and escape through binding with its ligand poliovirus receptor (PVR)
Engagement of TIGIT with PVR has been involved in modulating the cytokine production of dendritic cells (DCs) and facilitating the polarization of pro-inflammatory M1 macrophages into anti-inflammatory M2 macrophages, which in turn lead to the inhibition of effector T cells and NK cells activation [13, 25,26,27]
Structural dynamics and hydrogen bond crosslinking of PVR The structural properties of TIGIT/PVR complex and PVR bound to poliovirus were summarized (Table 1), and crystal structure of 3UDW was chosen based on the resolved resolution, R-value, and mutation sites introduced in the crystal structure to study the binding of PVR and TIGIT
Summary
TIGIT, as a novel immune checkpoint molecule involved in T cell and NK cell anergy, could induce the immune tolerance and escape through binding with its ligand PVR. Cytotoxic lymphocytes have been involved in the resistance of tumorigenesis and carcinogenesis process through cell-mediated immunity during cancer immunotherapy [1,2,3]. Cytotoxic lymphocytes, such as natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), TIGIT, with a full name of T cell immunoglobulin and ITIM domain ( known as WUCAM, Vstm or VSIG9), is an immunosuppressive receptor. The identified ligands of TIGIT contain CD155 ( known as PVR or nectin-like 5), CD112 and CD113 [15, 18, 19]. Antibodies targeting TIGIT/PVR pathway have achieved good clinical results in cancer treatment, as so far six TIGIT-targeting antibodies were under pre-clinical or clinical trials [33, 34]
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