“…The tumor tissues with the upregulated expression of TIGIT also exhibited aberrant immune characteristics. For example, in colorectal tumor tissues, TIGIT+ CD8+ T cells exhibited significantly higher infiltration and an exhausted phenotype with lower expression of proinflammtory cytokines and higher expression of inhibitory receptors such as PD-1, LAG-3, and TIM-3 on the surface 40 . Interestingly, according to our GSEA analysis, TIGIT was also shown the capability for driving the negative regulation on immune-related function and pathway, such as cytokine-cytokine receptor interaction, chemokine signaling pathway and natural killer cell mediated cytotoxicity, interferon-gamma response and IL6-JAK-STAT3 signaling.…”
T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown. Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with pathological stages, tumor-infiltrating immune cells (TIICs), signatures of T cells subtypes, immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS, HNSC, SKCM. TIGIT expression positively correlated with advanced stages, TIICs, the signatures of effector T cells, exhausted T cells, effector Tregs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also positively correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation. These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.
“…The tumor tissues with the upregulated expression of TIGIT also exhibited aberrant immune characteristics. For example, in colorectal tumor tissues, TIGIT+ CD8+ T cells exhibited significantly higher infiltration and an exhausted phenotype with lower expression of proinflammtory cytokines and higher expression of inhibitory receptors such as PD-1, LAG-3, and TIM-3 on the surface 40 . Interestingly, according to our GSEA analysis, TIGIT was also shown the capability for driving the negative regulation on immune-related function and pathway, such as cytokine-cytokine receptor interaction, chemokine signaling pathway and natural killer cell mediated cytotoxicity, interferon-gamma response and IL6-JAK-STAT3 signaling.…”
T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), an immune checkpoint, plays a pivotal role in immune suppression. However its role in tumor immunity and correlation with the genetic and epigenetic alterations remains unknown. Here, we comprehensively analyzed the expression patterns of the TIGIT and its value of prognostic prediction among 33 types of cancers based on the data collected from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression projects (GTEx). Furthermore, the correlations of TIGIT with pathological stages, tumor-infiltrating immune cells (TIICs), signatures of T cells subtypes, immune checkpoint genes, the degree of Estimation of STromal and Immune cells in MAlignant Tumor tissues using the Expression data (ESTIMATE), tumor mutation burden (TMB), microsatellite instability (MSI), mismatch repair (MMR) genes, and DNA methyltransferases (DNMTs) were also explored. Gene functional enrichment was conducted by Gene Set Enrichment Analysis (GSEA). Our results showed that the expression of TIGIT was upregulated in most of the cancer types. Cox regression model showed that high expression of TIGIT in tumor samples correlates with poor prognosis in KIRC, KIRP, LGG, UVM, and with favorable prognosis in BRCA, CECS, HNSC, SKCM. TIGIT expression positively correlated with advanced stages, TIICs, the signatures of effector T cells, exhausted T cells, effector Tregs and the degree of ESTIMATE in KIRC, KIRP and UVM. TIGIT expression also positively correlated with CTLA4, PDCD1 (PD-1), CD274 (PD-L1), ICOS in most of the cancer types. Furthermore, the expression of TIGIT was correlated with TMB, MSI, MMR genes and DNMTs in different types of cancers. GSEA analysis showed that the expression of TIGIT was related to cytokine-cytokine receptor interaction, allograft rejection, oxidative phosphorylation. These findings suggested that TIGIT could serve as a potential biomarker for prognosis and a novel target for immunotherapies in cancers.
“…In fact, −21 M HLA-B allotypes conditioned TCR-mediated response of CD8 + T lymphocytes, potentiating their proliferative capacity and restricting the stimulation-induced TIGIT over-expression, which is an inhibitory receptor that, according to our own and others’ results, can restrain the expansion of CD8 + T cells and modulate negatively their antitumor response. 51 , 52 A diagram summarizing our results is shown in Figure 6 . Figure 6.…”
NK and CD8
+
T cells are the main cytolytic effectors involved in innate and adaptive tumor immune surveillance, respectively. Although their educational pathways differ, similarities in their development and function suggest that CD8
+
T lymphocytes could be sensitive to NK cell licensing signals, which might influence their antitumor response. To demonstrate this hypothesis, we retrospectively evaluated the impact that NK cell licensing interactions have on the expression of CD226 on CD8
+
T lymphocytes and on the survival of patients with different hematopoietic and solid cancers (n = 1,023). Prospectively, we analyzed by multiparametric flow cytometry the anti-CD3/CD28-induced proliferation and immune-receptor expression of purified CD8
+
T lymphocytes from healthy donors (
n
= 17) with different combinations of NK cell licensing ligands. Results show that methionine/threonine (M/T) dimorphism at position −21 of the HLA-B leader peptide, but not other HLA class-I dimorphisms involved in the education of NK cells (HLA-C1/C2 or HLA-Bw4), is associated with greater survival and expression of CD226 in cancer patients, which was proportional to the number of methionines present in their genotype. CD8
+
T lymphocytes from healthy donors with −21 M showed higher proliferation rates and lower expression of TIGIT after
in vitro
stimulation. Therefore, CD8
+
T lymphocytes, like NK cells, appear to be sensitive to the −21 M/T dimorphism of HLA-B leader peptide, which results in the modulation of CD226
in vivo
and the proliferation and expression of TIGIT after
in vitro
stimulation, all of which could be related to their immune-surveillance capacity and the survival of cancer patients.
“…TIGIT + of CD8 + cell demonstrated expression at low levels for killer cytokines such as IL-2, TNF-α, and IFN-γ and an increase in the inhibitory receptors such as LAG-3, PD-1, and TIM-3 on the surface of TIGIT + of CD8 + cell. The accumulation of TIGIT + in T cells of patients with colorectal cancer was associated with more advanced disease conditions, predictable early recurrence, and decreased survival rates so that TIGIT could be a marker, a prognostic determinant, and a potential target in the colorectal cancer treatment [12]. In the following discussion, the researchers conducted drug-like properties analysis using Lipinski's rule of five and toxicity profile analysis of the test compounds from robusta coffee.…”
Objectives: This research aims to determine the efficacy of compounds in robusta coffee against colorectal cancer through the inhibition of the T-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) receptor.
Methods: This in silico study has been conducted in computing platform from June to August 2021. The selected test compounds would go through the Lipinski rule screening through the SwissADME website and the compounds that met these regulations would be docked to the TIGIT protein using AutoDock Tools and AutoDock Vina. The interactions with the highest binding energies were visualized using BIOVIA Discovery Studio 2020. The test compounds then underwent a toxicity profile analysis on the admetSAR 2.0 website.
Results: All test compounds complied with the Lipinski rule. The molecular docking results showed the highest binding energy in kahweol and cafestol (−8.1 kcal/mol) compared to OMC (−7.9 kcal/mol), chlorogenic acid (−7.8 kcal/mol), caffeic acid (−6.3 kcal/mol), caffeine (−6.1 kcal/mol), trigonelline (−5.3 kcal/mol), HMF (−5.1 kcal/mol), furfuryl alcohol (−4.4 kcal/mol), and 5-fluorouracil as the comparator drug (−5.3 kcal/mol). Kahweol, cafestol, and 5-fluorouracil revealed the hydrophobic interactions and hydrogen bonds with amino acid residues in TIGIT. Kahweol and cafestol unveiled minimal toxicity prediction
Conclusion: Kahweol and cafestol demonstrated the best results in inhibiting the TIGIT protein which played a role in colorectal cancer. In vitro and in vivo studies are needed to strengthen the findings of this research.
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