TIM-3 and TIGIT are possible immune checkpoint targets in patients with bladder cancer.
Ontology highlight
ABSTRACT:
SUBMITTER: Attalla K
PROVIDER: S-EPMC7980780 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain (TIGIT) is a newly discovered immune checkpoint molecule, mainly expressed on the surface of T cells and natural killer (NK) cells. By binding to cluster of differentiation 155 (CD155) and other ligands, it inhibits T cell and NK cell-mediated immune responses and affects the tumor microenvironment. Multiple preclinical studies have demonstrated that the TIGIT/CD155 pathway plays a role in a variety of solid and hematological tumors. Clinical trials investigating TIGIT inhibitors alone or in combination with programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors for lung cancer are currently underway.
.
| S-EPMC9720676 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) has an extremely poor prognosis and is one of the most common malignancies worldwide. Immune checkpoint suppression has become the most effective treatment option for liver cancer. The strategies used for immune checkpoint inhibitor targeting cancer therapies have been affected by some significant successes, including blocking the advanced-stage malignant tumor by death protein 1 (PD-1)/programmed cell death ligand (PDL-1), and cytotoxic T-lymphocyte antigen-4 (CTLA4) pathways. T cell immunoreceptor with immunoglobulin and ITIM domains (TIGIT) is an immune checkpoint that participates in tumor immune surveillance. Mainly expressed on T cells, natural killer (NK) cells, and other antigen-presenting cells (APCs), it diminishes cytokine production and exhibits strong suppressive properties. TIGIT achieves a more active antitumor immune response and highlights a pivotal role for cancer immunotherapy. Preclinical studies have found inhibitory effects using a targeted approach. Monotherapy targeting TIGIT or in combination with anti-PD-1/PD-L1 monoclonal antibodies for the treatment of patients with advanced solid malignancies have demonstrated improved antitumor immune responses. Due to the high tumor heterogeneity of liver cancer, immune checkpoint suppression therapy still needs further exploration. Therefore, we provide insights into the characteristics of TIGIT and the immune system in HCC.
| S-EPMC7407725 | biostudies-literature
Project description:Tim-1, a phosphatidylserine receptor expressed on B cells, induces interleukin 10 (IL-10) production by sensing apoptotic cells. Here we show that mice with B cell-specific Tim-1 deletion develop tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Transcriptomic analysis demonstrates that besides IL-10, Tim-1+ B cells also differentially express a number of co-inhibitory checkpoint receptors including TIGIT. Mice with B cell-specific TIGIT deletion develop spontaneous paralysis with CNS inflammation, but with limited inflammation in other organs. Our findings suggest that Tim-1+ B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 signaling-dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. A possible critical role of aryl hydrocarbon receptor (AhR) in regulating the B cell function is discussed, as we find that AhR is among the preferentially expressed transcription factors in Tim-1+ B cells and regulates their TIGIT and IL-10 expression.
| S-EPMC7496220 | biostudies-literature
Project description:T cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on several types of lymphocytes. Efficacy of antibody blockade of TIGIT in cancer immunotherapy is currently widely being investigated in both pre-clinical and clinical studies. In multiple cancers TIGIT is expressed on tumor-infiltrating cytotoxic T cells, helper T cells, regulatory T cells and NK cells, and its main ligand CD155 is expressed on tumor-infiltrating myeloid cells and upregulated on cancer cells, which contributes to local suppression of immune-surveillance. While single TIGIT blockade has limited anti-tumor efficacy, pre-clinical studies indicate that co-blockade of TIGIT and PD-1/PD-L1 pathway leads to tumor rejection, notably even in anti-PD-1 resistant tumor models. Among inhibitory immune checkpoint molecules, a unique property of TIGIT blockade is that it enhances not only anti-tumor effector T-cell responses, but also NK-cell responses, and reduces the suppressive capacity of regulatory T cells. Numerous clinical trials on TIGIT-blockade in cancer have recently been initiated, predominantly combination treatments. The first interim results show promise for combined TIGIT and PD-L1 co-blockade in solid cancer patients. In this review, we summarize the current knowledge and identify the gaps in our current understanding of TIGIT's roles in cancer immunity, and provide, based on these insights, recommendations for its positioning in cancer immunotherapy.
| S-EPMC8339559 | biostudies-literature
Project description:In one decade, immunotherapy based on immune checkpoint blockades (ICBs) has become a new pillar of cancer treatment following surgery, radiation, chemotherapy, and targeted therapies. However, not all cancer patients benefit from single or combination therapy with anti-CTLA-4 and anti-PD-1/PD-L1 monoclonal antibodies. Thus, an increasing number of immune checkpoint proteins (ICPs) have been screened and their effectiveness evaluated in preclinical and clinical trials. Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain-containing-3 (TIM-3), and T cell immunoreceptor with immunoglobulin and tyrosine-based inhibitory motif (ITIM) domain (TIGIT) constitute the second wave of immunotherapy targets that show great promise for use in the treatment of solid tumors and leukemia. To promote the research and clinical application of ICBs directed at these targets, we summarize their discovery, immunotherapy mechanism, preclinical efficiency, and clinical trial results in this review.
| S-EPMC10478462 | biostudies-literature
Project description:Tim-1, a phosphatidylserine receptor expressed on B cells induces IL-10 production by sensing apoptotic cells. Here we show that mice with B cell-specific Tim-1 deletion developed tissue inflammation in multiple organs including spontaneous paralysis with inflammation in the central nervous system (CNS). Transcriptomic analysis demonstrated that besides IL-10, Tim-1+ B cells also differentially expressed a number of co-inhibitory “checkpoint” receptors including TIGIT. Mice with B cell-specific TIGIT deletion developed spontaneous paralysis with CNS inflammation but with limited inflammation in other organs. Our findings suggest that Tim-1+ B cells are essential for maintaining self-tolerance and restraining tissue inflammation, and that Tim-1 dependent TIGIT expression on B cells is essential for maintaining CNS-specific tolerance. A possible critical role of AhR in regulating the B cell function is discussed, as we found that AhR is a top-ranked transcription factor expressed in Tim-1+ B cells and regulates their TIGIT and IL-10 expression.
2020-08-31 | GSE150786 | GEO
Project description:Checkpoint inhibitors have become an efficient way to treat cancers. Indeed, anti-CTLA-4, anti-PD1, and anti-PDL-1 antibodies are now used as therapies for cancers. However, while these therapies are very efficient in certain tumors, they remain poorly efficient in others. This might be explained by the immune infiltrate, the expression of target molecules, and the influence of the tumor microenvironment. It is therefore critical to identify checkpoint antigens that represent alternative targets for immunotherapies. PVR-like molecules play regulatory roles in immune cell functions. These proteins are expressed by different cell types and have been shown to be upregulated in various malignancies. PVR and Nectin-2 are expressed by tumor cells as well as myeloid cells, while TIGIT, CD96, and DNAM-1 are expressed on effector lymphoid cells. PVR is able to bind DNAM-1, CD96, and TIGIT, which results in two distinct profiles of effector cell activation. Indeed, while binding to DNAM-1 induces the release of cytokines and cytotoxicity of cytotoxic effector cells, binding TIGIT induces an immunosuppressive and non-cytotoxic profile. PVR is also able to bind CD96, which induces an immunosuppressive response in murine models. Unfortunately, in humans, results remain contradictory, and this interaction might induce the activation or the suppression of the immune response. Similarly, Nectin-2 was shown to bind TIGIT and to induce regulatory profiles in effectors cells such as NK and T cells. Therefore, these data highlight the potential of each of the molecules of the "PVR-TIGIT axis" as a potential target for immune checkpoint therapy. However, many questions remain to be answered to fully understand the mechanisms of this synapse, in particular for human CD96 and Nectin-2, which are still understudied. Here, we review the recent advances in "PVR-TIGIT axis" research and discuss the potential of targeting this axis by checkpoint immunotherapies.
| S-EPMC7222031 | biostudies-literature
Project description:Bladder cancer remains the most immunogenic and expensive malignant tumor in the United States today. As the 4th leading cause of death from cancer in United States, Immunotherapy blocking immune checkpoints have been recently been applied to many aggressive cancers and changed interventions of urological cancers including advanced bladder cancer. The applied inhibition of PD-1-PD-L1 interactions can restore antitumor T-cell activity and enhance the cellular immune attack on antigens. The overall goals of this short review article are to introduce current cancer immunotherapy and immune checkpoint inhibitors, and to provide new insight into the underlying mechanisms that block immune checkpoints in tumor microenvironment. Furthermore, this review will address the preclinical and clinical trials to determine whether bladder cancer patients could benefit from this new cancer therapy in near future.
| S-EPMC4910761 | biostudies-literature
Project description:Immune checkpoints are intensively investigated as targets in cancer therapy. T-cell immunoreceptor with immunoglobulin (Ig) and ITIM domains (TIGIT) and its ligand poliovirus receptor (PVR) are recently emerging as novel promising targets in immunotherapy. Here, we show that high expression of PVR represents an independent prognostic marker being associated with poor outcome for breast cancer patients. Furthermore, PVR mRNA, as well as protein expression, is associated with more aggressive breast cancer subtypes such as HER2 positive and triple-negative breast cancer. In vitro, blocking TIGIT or PVR resulted in enhanced immune cell-mediated lysis of breast cancer cell lines SKBR-3, MDA-MB-231, MDA-MB-468, and BT549 and additionally increased the cytotoxic effects of a bispecific T cell engager BiTE® antibody construct targeting EGFR. Taken together, our data identify the immune checkpoint factor PVR as a novel prognostic marker in breast cancer and indicate that blocking the TIGIT-PVR axis might represent a novel therapeutic option for the treatment of breast cancer patients.
| S-EPMC6844319 | biostudies-literature
Project description:BackgroundInhibitors targeting immune checkpoint were proved effective in cancer immunotherapy, such as PD-1/PD-L1 blockade. The novel immune checkpoint TIGIT/PVR plays critical roles in suppressing the anti-tumor effects of CD8+ T and NK cells, and dual blockade of TIGIT/PVR and PD-1/PD-L1 by antibody can elicit synergistic effects in tumor models and clinical trials. However, small molecules for TIGIT/PVR blockade have not been investigated.MethodsThe expression of PVR in tumors were analyzed by using TCGA, Oncomine and GEO database, and in cancer cell lines examined by flow cytometry. Natural product compounds were docked to PVR for virtual screening by using the software Molecular Operating Environment (MOE). Candidate compounds were further tested by biolayer interferometry-based binding assay, microscale thermophoresis assay and cell based blocking assay. The in vitro activity of the candidate compound was determined by MTT, peripheral blood mononuclear cells (PBMCs) activation assay and coculture assay. The anti-tumor effects and mechanism were also investigated by using MC38 tumor-bearing mice model and immune cell depletion tumor model.ResultsPVR was over-expressed in many tumor tissues and cancer cell lines, making it a promising therapeutic target. Through virtual screening, binding, and blocking assay, liothyronine was discovered to bind PVR and block the interaction of TIGIT/PVR. Liothyronine could enhance the function of CD4+ and CD8+ T cells in PBMCs. Besides, in the Jurkat-hTIGIT and CHOK1-hPVR coculture assay, liothyronine could reverse the IL-2 secretion inhibition resulted by TIGIT/PVR ligation. Although had no influence on the proliferation of tumor cells in vitro, liothyronine could significantly inhibit tumor growth when administrated in vivo, by enhancing CD8+ T cell infiltration and immune responses in the tumor bearing mice. The immune cell depletion model showed that the anti-tumor effects of liothyronine depends on CD4+ T cells, CD8+ T cells and NK cells.ConclusionsA small molecule liothyronine was discovered to serve as a potential candidate for cancer immunotherapy by blocking the immune checkpoint TIGIT/PVR. Video abstract.
| S-EPMC7487564 | biostudies-literature