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.
Subject(s)
Bile Duct Neoplasms/genetics , Bile Duct Neoplasms/immunology , CD8-Positive T-Lymphocytes/immunology , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/immunology , Cholangiocarcinoma/genetics , Cholangiocarcinoma/immunology , Liver Neoplasms/genetics , Liver Neoplasms/immunology , Receptors, Immunologic/genetics , Transcriptome , Aged , Animals , Bile Duct Neoplasms/pathology , Biomarkers, Tumor/genetics , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/pathology , Cell Line, Tumor , Cholangiocarcinoma/pathology , Disease Models, Animal , Drug Therapy, Combination , Female , Gene Expression Profiling/methods , Humans , Immune Checkpoint Inhibitors/therapeutic use , Liver Neoplasms/drug therapy , Liver Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating/immunology , Male , Mice , Mice, Inbred C57BL , Middle Aged , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Receptors, Immunologic/antagonists & inhibitors , Treatment Outcome , Tumor Burden/drug effectsABSTRACT
BACKGROUND AND OBJECTIVE: Goal was to evaluate the potential of in vivo optical coherence tomography (OCT) imaging to determine the response of patients with xerostomia to a dry mouth toothpaste versus fluoride toothpaste placebo. STUDY DESIGN/MATERIALS AND METHODS: Ten subjects with xerostomia participated in this double-blind, crossover, placebo-controlled study. After examination and OCT imaging, subjects used the first product for 15 days, followed by a 7-day washout period, and then they used the second product for 15 days. Data were acquired at 5-day intervals, also before and after the washout. RESULTS: Visual examination and tongue blade adhesion test did not reflect response to the product. Two imaging-based markers were identified: (i) In OCT images, epithelial thickness increased significantly (P < 0.05) after use of the dry mouth toothpaste, but did not change significantly (P > 0.05) after the use of a fluoride toothpaste and (2) Optical backscattering data showed progressive characteristic changes from baseline with use of the active product. CONCLUSIONS: In this pilot study using in vivo OCT imaging, it was possible to detect and measure oral epithelial response to the dry mouth product versus placebo in patients with xerostomia. CLINICAL IMPLICATIONS: This approach may permit site-specific assessment of xerostomia, individualized treatment planning and monitoring, and sequential mucosal mapping in patients with dry mouth.
