Transcriptome Profiling Identifies TIGIT as a Marker of T‐Cell Exhaustion in Liver Cancer

Abstract

BACKGROUND AND AIMS Programmed death 1 (PD‐1) checkpoint inhibition has shown promising results in patients with hepatocellular carcinoma, inducing objective responses in approximately 20% of treated patients. The roles of other coinhibitory molecules and their individual contributions to T‐cell dysfunction in liver cancer, however, remain largely elusive. APPROACH AND RESULTS We performed a comprehensive mRNA profiling of cluster of differentiation 8 (CD8) T cells in a murine model of autochthonous liver cancer by comparing the transcriptome of naive, functional effector, and exhausted, tumor‐specific CD8 T cells. Subsequently, we functionally validated the role of identified genes in T‐cell exhaustion. Our results reveal a unique transcriptome signature of exhausted T cells and demonstrate that up‐regulation of the inhibitory immune receptor T‐cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibitor motif domains (TIGIT) represents a hallmark in the process of T‐cell exhaustion in liver cancer. Compared to PD‐1, expression of TIGIT more reliably identified exhausted CD8 T cells at different stages of their differentiation. In combination with PD‐1 inhibition, targeting of TIGIT with antagonistic antibodies resulted in synergistic inhibition of liver cancer growth in immunocompetent mice. Finally, we demonstrate expression of TIGIT on tumor‐infiltrating CD8 T cells in tissue samples of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma and identify two subsets of patients based on differential expression of TIGIT on tumor‐specific T cells. CONCLUSIONS Our transcriptome analysis provides a valuable resource for the identification of key pathways involved in T‐cell exhaustion in patients with liver cancer and identifies TIGIT as a potential target in checkpoint combination therapies.

TIGIT + TIM-3 + NK cells are correlated with NK cell exhaustion and disease progression in patients with hepatitis B virus‑related hepatocellular carcinoma

“…27,28 In a variety of tumors, the co-inhibitory molecules TIGIT and TIM-3 are closely related to T cell exhausted. [29][30][31][32] These studies indicate that it is necessary to study the specific exhausted phenotype and function of NK cells in HBV-HCC patients to reveal new anti-tumor targets of NK cells. In this study, we found that the co-expression of TIGIT and TIM-3 mediates NK cells exhaustion in HBV-HCC patients, which is characterized by the decrease of cytokine (IFN-γ, TNF-α), decreased cytotoxicity (CD107a), proliferation (Ki67), and high expression of T-bet lo Eomes hi NK cells in HBV-HCC patients.…”

Hitting the complexity of the TIGIT-CD96-CD112R-CD226 axis for next-generation cancer immunotherapy

“…TIGIT activation in Treg cells leads to T-cell suppression by producing interleukin (IL)-10 and fibrinogen-like protein 2 (35,36). TIGIT expression and clinical outcomes in cancer: Increased TIGIT expression on TILs has been observed in various human cancers, including non-small-cell lung carcinoma (NSCLC), melanoma, head and neck squamous cell carcinoma (HNSCC), colorectal cancer (CRC), glioblastoma (GBM), gastric cancer, liver cancer, multiple myeloma (MM), acute myeloid leukemia (AML), and follicular lymphoma (FL) (15,(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47). TIGIT-expressing CD8 is correlated with AML relapse and post-allogeneic stem-cell transplantation progression (38).…”

The therapeutic landscape of hepatocellular carcinoma

“…248 Unfortunately, T cell activity in tumors is limited; chronic stimulation of T cells ultimately leads to a dysfunctional state called T cell exhaustion that has been associated with high levels of PD-1 expression and a low responsiveness to checkpoint blockade. [249][250][251][252] Inhibition of PD-1/PD-L1 can lead to reinvigoration of exhausted T cells and improvement of their anti-tumor activity. 253 Nevertheless, it seems that certain properties of exhausted T cells cannot be reverted.…”