Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS

Lucca, Liliana E.; Lerner, Benjamin A.; Park, Calvin; DeBartolo, Danielle; Harnett, Brian; Kumar, Varun P.; Ponath, Gerald; Raddassi, Khadir; Hüttner, Anita; Hafler, David A.; Pitt, David

doi:10.1212/nxi.0000000000000712

Cited by 26 publications

(24 citation statements)

References 28 publications

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“…Several recent reports characterize the severe exhaustion signature of T-cells in glioblastoma [ 48 ] and functional hyporesponsiveness [ 49 ]. It has been proposed that distinct co-inhibitory mechanisms are involved; besides the PD-L1/PD-1 axis, LAG3 and, more recently, TIGIT have been detected in glioblastoma T-cells [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical Characterization of Immune Infiltrate in Tumor Microenvironment of Glioblastoma

Rahimi

Minasi

Ugolini

et al. 2020

JPM

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Background: Glioblastoma (GBM) is the most common primary malignant brain cancer in adults, with very limited therapeutic options. It is characterized by a severe immunosuppressive milieu mostly triggered by suppressive CD163+ tumor-associated macrophages (TAMs). The efficacy of immune checkpoint inhibitor interventions aimed at rescuing anti-tumor immunity has not been proved to date. Thus, it is critically important to investigate the immunomodulatory mechanisms acting within the GBM microenvironment for the better design of immunotherapeutic strategies. Methods: The immunohistochemical analysis of a panel of immune biomarkers (CD3, FoxP3, CD163, IDO, PDL-1, PD-1 and TIGIT) was performed in paired samples of the tumor core (TC) and peritumoral area (PTA) of nine GBM patients. Results: CD163+ cells were the most common cell type in both the PTA and TC. IDO and PDL-1 were expressed in most of the TC samples, frequently accompanied by TIGIT expression; on the contrary, they were almost absent in the PTA. CD3+ cells were present in both the TC and PTA, to a lesser extent than CD163+ cells; they often were accompanied by PD-1 expression, especially in the TC. FoxP3 was scarcely present. Conclusion: Distinct inhibitory mechanisms can act simultaneously in both the TC and PTA to contribute to the strong immunosuppression observed within the GBM microenvironment. Nevertheless, the PTA shows strongly reduced immunosuppression when compared to the TC, thus representing a potential target for immunotherapies. Moreover, our results support the working hypothesis that immunosuppression and T-cell exhaustion can be simultaneously targeted to rescue anti-tumor immunity in GBM patients.

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical Characterization of Immune Infiltrate in Tumor Microenvironment of Glioblastoma

Rahimi

Minasi

Ugolini

et al. 2020

JPM

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“…no. 76437; Cell Signaling Technology, Inc.) ( 16 ), and incubated overnight at 4°C. PBS replaced the primary antibodies as a negative control.…”

Section: Methodsmentioning

confidence: 99%

B3GNT3: A prognostic biomarker associated with immune cell infiltration in pancreatic adenocarcinoma

et al. 2020

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Pancreatic cancer, one of the most malignant gastrointestinal tumors, is prone to liver metastasis. However, due to the lack of appropriate and comprehensive diagnostic methods, it is difficult to accurately predict the survival outcomes. Therefore, there is a need to identify effective biomarkers, such as UDP-GlcNAc: βGal β-1,3-N-acetylglucosaminyltransferase 3 ( B3GNT3 ), that predict the survival outcome of patients with pancreatic cancer. In the present study, based on data from 171 cases of pancreatic cancer obtained from The Cancer Genome Atlas portal, the differential expression of mRNAs was screened by comparing cancerous tissues with adjacent tissues. Univariate Cox regression analysis demonstrated that B3GNT3 had prognostic capability and could be an independent prognostic factor for pancreatic adenocarcinoma (PAAD). Using the Tumor Immune Estimation Resource tool and Tumor-Immune System Interaction Database, a potential relationship between B3GNT3 expression and immune cell infiltration was identified in pancreatic carcinoma. Furthermore, 177 samples of pancreatic carcinoma were collected and the association of CD68 expression with B3GNT3 was assessed by immunohistochemical staining. B3GNT3 expression was associated with clinical outcomes in pancreatic carcinoma and related to infiltrating levels of immune cells, which indicated that B3GNT3 could be used as an immunotherapy target for PAAD.

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“…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 - 47 ). TIGIT-expressing CD8 + TILs are most likely in an exhausted state characterized by high co-expression of inhibitory immune checkpoint receptors, such as PD-1, lymphocyte-activation gene 3 (LAG-3), T-cell immunoglobulin, and mucin-domain containing-3 (TIM-3), and have an impaired capacity to proliferate and produce cytokines ( 34 , 48 - 50 ).…”

Section: Tigit Family Of Receptorsmentioning

confidence: 99%

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

Jin

Park

2021

BMB Rep.

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Antibody-based therapeutics targeting the inhibitory receptors PD-1, PD-L1, or CTLA-4 have shown remarkable clinical progress on several cancers. However, most patients do not benefit from these therapies. Thus, many efforts are being made to identify new immune checkpoint receptor-ligand pathways that are alternative targets for cancer immunotherapies. Nectin and nectin-like molecules are widely expressed on several types of tumor cells and play regulatory roles in T- and NK-cell functions. TIGIT, CD226, CD96 and CD112R on lymphoid cells are a group of immunoglobulin superfamily receptors that interact with Nectin and nectin-like molecules with different affinities. These receptors transmit activating or inhibitory signals upon binding their cognate ligands to the immune cells. The integrated signals formed by their complex interactions contribute to regu-lating immune-cell functions. Several clinical trials are currently evaluating the efficacy of anti-TIGIT and anti-CD112R blockades for treating patients with solid tumors. However, many questions still need to be answered in order to fully understand the dynamics and functions of these receptor networks. This review addresses the rationale behind targeting TIGIT, CD226, CD96, and CD112R to regulate T- and NK-cell functions and discusses their potential application in cancer immunotherapy.

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Differential expression of the T-cell inhibitor TIGIT in glioblastoma and MS

Cited by 26 publications

References 28 publications

Immunohistochemical Characterization of Immune Infiltrate in Tumor Microenvironment of Glioblastoma

Immunohistochemical Characterization of Immune Infiltrate in Tumor Microenvironment of Glioblastoma

B3GNT3: A prognostic biomarker associated with immune cell infiltration in pancreatic adenocarcinoma

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

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