Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer

Abstract

Objective TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer. Methods The expression of CD155 and TIGIT in cervical cancer tissues was detected using flow cytometry, immunohistochemistry (IHC) and gene expression profiling. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Changes in the NF-κB and ERK pathways were detected using western blotting (WB) after blocking TIGIT/CD155 signalling. Results TIGIT expression was elevated in patients with cervical cancer. High TIGIT expression in CD8+ T lymphocytes from patients with cervical cancer promotes the exhaustion of CD8+ T lymphocytes. In addition, CD155 is expressed at high levels in cervical cancer tissues and is negatively correlated with the level of infiltrating CD8+ T cells. We found that TIGIT, upon binding to CD155 and being phosphorylated, inhibited NF-κB and ERK activation by recruiting SHIP-1, resulting in the downregulation of cytokine production. Blocking TIGIT in activated CD8+ T cells attenuates the inhibitory effect of SHIP-1 on CD8+ T cells and enhances the activation of NF-κB and ERK. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Injecting the blocking antibody TIGIT in vivo inhibits tumour growth and enhances CD8+ T lymphocyte function. Treatment with a combination of TIGIT and PD-1 inhibitors further increases the efficacy of the TIGIT blocking antibody. Conclusions Our research shows that TIGIT/CD155 is a potential therapeutic target for cervical cancer.

Establishment and validation of exhausted CD8+ T cell feature as a prognostic model of HCC

“…These transcription factors include: ILF3, RFXANK, RFXAP, RFX5, CIITA, RELA, NFKB1, AR, E2F1, STAT3 and JUN. Consistent with the conclusions of other studies, NFKB1/RelA heterodimers participated in NF-kB signaling pathway activation, which is an important factor for Tex production (35)(36)(37). Transcription factors CIITA, RFX5, RFXAP, and RFXANK mutations have been associated with Major histocompatibility complex (MHC) II deficiency, so they're also associated with immune exhaustion.…”

Nectin Family Ligands Trigger Immune Effector Functions in Health and Autoimmunity

“…Although altered expression profiles of DNAM-1, CRTAM, Tactile and TIGIT are reported in peripheral blood samples of patients diagnosed with MS, RA, SSc, psoriasis, etc., a correlation with disease severity and progression in time is often lacking. In addition, modulating the DNAM-1/TIGIT axis is highly investigated as a therapeutic target in oncoimmunity, and can also be of interest to target autoimmunity to boost immunoregulation and reduce target-cell killing [ 104 , 105 ]. Furthermore, genetic variants of DNAM-1 [ 22 ], CRTAM [ 72 ] and Tactile [ 94 ] are identified as being related to autoimmune susceptibility, the hub gene for diagnosis and unresponsiveness to immunosuppressive therapies, which underscores the importance of further genome-wide association studies in this field.…”

“…Herein, TIGIT triggering by Necl-5 + target cells results in the disruption of granule polarization through the recruitment of SHIP1 by its ITT-like motif [ 3 , 9 , 103 ]. Similarly, SHIP1 recruitment to TIGIT on CD8 + CTLs results in reduced secretion of granzyme B, TNF-α and IFN-γ due to inhibition of ERK, MAPK and transcription factor NF-κB [ 104 ]. Blockage of the TIGIT–Necl-5 interaction restores the impaired NK cell and CD8 + CTL effector function.…”

“…Blockage of the TIGIT–Necl-5 interaction restores the impaired NK cell and CD8 + CTL effector function. This mechanism is often used by tumors, which upregulate Necl-5 and Nectin-2, to evade a cytotoxic response [ 104 , 105 ]. TIGIT can allegedly also bind to Nectin-3, however, there are currently no clear effector functions described for this interaction [ 103 ].…”

Monoclonal antibodies in cervical malignancy-related HPV

“…In other words, by interacting with three ligands (CD155, CD112, and CD113) expressed on the surface of tumor cells, TIGIT causes the immune system to be suppressed ( 120 ). In this regard, Liu et al., in 2022, demonstrated that TIGIT is a novel therapeutic target in cervical malignancy; additionally, it plays a significant role in preclinical models of cervical cancer following inhibition of TIGIT by monoclonal antibodies, both alone and in combination with anti-PD-1/PD-L1 antibodies ( 121 ). On the other hand, similar to PD-1/PD-L1, TIGIT plays a role in inhibiting the tumor immune system and both are upregulated in different types of malignancies ( 119 ).…”