Background T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) is a checkpoint receptor thought to be involved in mediating T-cell exhaustion and dysfunction of natural killer (NK) cells in tumours and is emerging as novel promising targets in immunotherapy, however, the ligand binding and the efficacy of its antibody still need to be further explored. Methods Four different TIGIT antibodies in characteristics of antigen binding, in vitro effects on activated T cells, Fc region functions and tumour inhibition in animal models were compared. The antibody as monotherapy and combined with anti-PD-L1 antibody, effects on PBMC in ex vivo coculture with autologous human CRC organoids as well as PK profile were evaluated. Results Studies demonstrated that TIGIT antibody with PVR-competitive ability as monotherapy resulted in inhibition of tumour growth, sustained anti-tumour immune memory in tumour re-challenge mice, enhanced anti-tumour therapy in combination with anti-PD-L1. Ex vivo coculture assay suggested that TIGIT antibody treatment activated immune cells and promoted infiltration and tumour killing ability of autologous PBMC in human CRC organoids. Conclusions Our study broadens the knowledge of TIGIT antibody in cancer immunotherapy and may benefit future development of next-generation checkpoint inhibitors with improved clinical outcomes.
Using entire tumor cells or tissues that display both common and patient-specific antigens can potentially trigger a comprehensive and long-lasting anti-tumor immune response. However, the limited immunogenicity, low uptake efficiency, and susceptibility to degradation of whole-component antigens present significant challenges. In this study, we employed tumor lysates (TLs) as whole-component antigens, in conjunction with MgAl-layered double hydroxide (MA) as nanoadjuvants and Mn 2+ as immunostimulants, to create personalized MMAT (Mn 2+ -MA-TLs) nanovaccines. After subcutaneous injection of MMAT nanovaccines, the high local concentrations of TLs and Mn 2+ facilitated the recruitment and activation of antigen-presenting cells (APCs), thereby inducing a robust adaptive immune response. Remarkably, MMAT nanovaccines enabled lysosomal escape, enhanced antigen cross-presentation, and activated the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway in APCs. Furthermore, MMAT nanovaccines, when combined with the anti-TIGIT monoclonal antibody (aTIGIT), an immune checkpoint inhibitor, not only stimulated T-cell-based adaptive anti-tumor immune responses but also activated the NK-cell-based innate anti-tumor immunity, effectively suppressing tumor growth, recurrence, and metastasis. Thus, the ternary MMAT nanovaccines developed here introduced a pioneered paradigm for the rapid preparation of whole-component tumor antigens with nanoadjuvants and immunostimulants into nanovaccines, offering new prospects for clinical immunotherapies.
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