Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy

Dodagatta-Marri, Eswari; Ma, Hsiao-Yen; Liang, Benjia; Li, John; Meyer, Dominique; Chen, Szu-Ying; Sun, Kan; Ren, Xin; Zivak, Bahar; Rosenblum, Michael D.; Headley, Mark B.; Pinzas, Lauren; Reed, Nilgun Isik; Cid, Joselyn S. Del; Hann, Byron; Yang, Sharon; Giddabasappa, Anand; Noorbehesht, Kavon; Yang, Bing; Porto, Joseph Dal; Tsukui, Tohru; Niessen, Kyle; Atakilit, Amha; Akhurst, Rosemary J.; Sheppard, Dean

doi:10.1016/j.celrep.2021.109309

Cited by 41 publications

(31 citation statements)

References 31 publications

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“…While data presented here suggest that therapeutics blocking α V β 8 integrin’s ability to activate TGF-β have great promise in preventing fibrotic PCO, unanswered questions remain. First, the function blocking antibody therapy used in this study was administered to the animals intravenously as the systemic administration of ADWA-11 showed no evidence of toxicity in prior studies ( 34 , 56 , 57 ), and a humanized version of ADWA-11 did not elicit notable systemic toxicity in mice and Cynomolgus monkeys treated for over 1 month at doses more than 5 times that used here ( 56 , 57 ). However, attempts to directly inject the ADWA-11 into the mouse capsular bag at surgery did not block the fibrotic transformation of LCs.…”

Section: Discussionmentioning

confidence: 86%

αVβ8 integrin targeting to prevent posterior capsular opacification

et al. 2021

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Fibrotic posterior capsular opacification (PCO), a major complication of cataract surgery, is driven by transforming growth factor β (TGFβ). Previously, αV integrins were found to be critical for the onset of TGFβ-mediated PCO in vivo, however, the functional heterodimer was unknown. Here, β8 integrin conditional knockout (β8ITGcKO) lens cells (LCs) were observed to attenuate their fibrotic responses, while both β5 and β6 integrin null LCs underwent fibrotic changes similar to WT at 5 days PCS. RNAseq revealed that β8ITGcKO LCs attenuated their upregulation of integrins and their ligands, as well as known targets of TGFβ induced signaling at 24 hours PCS. Treatment of β8ITGcKO eyes with active TGFβ1 at the time of surgery rescued the fibrotic response. Treatment of wild type mice with an anti-αVβ8 integrin function blocking antibody at the time of surgery ameliorated both canonical TGFβ signaling and LC fibrotic response PCS, and treatment at 5 days PCS, after surgically induced fibrotic responses are established, largely reversed this fibrotic response. These data suggest that αVβ8 integrin is a major regulator of TGFβ activation by LCs PCS and that therapeutics targeting αVβ8 integrin could be effective for fibrotic PCO prevention and treatment.

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Section: Discussionmentioning

confidence: 86%

αVβ8 integrin targeting to prevent posterior capsular opacification

et al. 2021

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“… 32 More interestingly, ITGB8 functions as a key driver of transforming growth factor b (TGF-b) to impede the antitumor immunity leading to the tumor growth. 33 …”

Section: Resultsmentioning

confidence: 99%

Integrated Transcriptome Profiling Identifies Prognostic Hub Genes as Therapeutic Targets of Glioblastoma: Evidenced by Bioinformatics Analysis

Nayak

2022

ACS Omega

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Glioblastoma (GBM) is the most devastating and frequent type of primary brain tumor with high morbidity and mortality. Despite the use of surgical resection followed by radio- and chemotherapy as standard therapy, the progression of GBM remains dismal with a median overall survival of <15 months. GBM embodies a populace of cancer stem cells (GSCs) that is associated with tumor initiation, invasion, therapeutic resistance, and post-treatment reoccurrence. However, understanding the potential mechanisms of stemness and their candidate biomarkers remains limited. Hence in this investigation, we aimed to illuminate potential candidate hub genes and key pathways associated with the pathogenesis of GSC in the development of GBM. The integrated analysis discovered differentially expressed genes (DEGs) between the brain cancer tissues (GBM and GSC) and normal brain tissues. Multiple approaches, including gene ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, were employed to functionally annotate the DEGs and visualize them through the R program. The significant hub genes were identified through the protein–protein interaction network, Venn diagram analysis, and survival analysis. We observed that the upregulated DEGs were prominently involved in the ECM–receptor interaction pathway. The downregulated genes were mainly associated with the axon guidance pathway. Five significant hub genes (CTNNB1, ITGB1, TNC, EGFR, and SHOX2) were screened out through multiple analyses. GO and KEGG analyses of hub genes uncovered that these genes were primarily enriched in disease-associated pathways such as the inhibition of apoptosis and the DNA damage repair mechanism, activation of the cell cycle, EMT (epithelial–mesenchymal transition), hormone AR (androgen receptor), hormone ER (estrogen receptor), PI3K/AKT (phosphatidylinositol 3-kinase and AKT), RTK (receptor tyrosine kinase), and TSC/mTOR (tuberous sclerosis complex and mammalian target of rapamycin). Consequently, the epigenetic regulatory network disclosed that hub genes played a vital role in the progression of GBM. Finally, candidate drugs were predicted that can be used as possible drugs to treat GBM patients. Overall, our investigation offered five hub genes (CTNNB1, ITGB1, TNC, EGFR, and SHOX2) that could be used as precise diagnostic and prognostic candidate biomarkers of GBM and might be used as personalized therapeutic targets to obstruct gliomagenesis.

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“…Recently, a study demonstrated that upregulation of integrin β8 mediated by lnc-TCF7 leads to ovarian cancer stemness ( 190 ). Integrin αvβ8, a key activator of TGF-β, regulates immunotherapy and radiotherapy resistance, which may be reversed by a potent blocking monoclonal antibody against integrin αvβ8 (ADWA-11) in prostate cancer ( 191 ). The anti-integrin β8 antibody treatment mechanism restores the in vitro cytotoxic effect of tumor CD8 T cells by inhibiting Treg cells ( 191 , 192 ).…”

Section: Integrin and Endocrine-related Cancersmentioning

confidence: 99%

Mechanisms of Cell Adhesion Molecules in Endocrine-Related Cancers: A Concise Outlook

et al. 2022

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Chemotherapy is a critical treatment for endocrine-related cancers; however, chemoresistance and disease recurrence remain a challenge. The interplay between cancer cells and the tumor microenvironment via cell adhesion molecules (CAMs) promotes drug resistance, known as cell adhesion-mediated drug resistance (CAM-DR). CAMs are cell surface molecules that facilitate cell-to-cell or cell-to-extracellular matrix binding. CAMs exert an adhesion effect and trigger intracellular signaling that regulates cancer cell stemness maintenance, survival, proliferation, metastasis, epithelial–mesenchymal transition, and drug resistance. To understand these mechanisms, this review focuses on the role of CD44, cadherins, selectins, and integrins in CAM-DR in endocrine-related cancers.

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Integrin αvβ8 on T cells suppresses anti-tumor immunity in multiple models and is a promising target for tumor immunotherapy

Cited by 41 publications

References 31 publications

αVβ8 integrin targeting to prevent posterior capsular opacification

αVβ8 integrin targeting to prevent posterior capsular opacification

Integrated Transcriptome Profiling Identifies Prognostic Hub Genes as Therapeutic Targets of Glioblastoma: Evidenced by Bioinformatics Analysis

Mechanisms of Cell Adhesion Molecules in Endocrine-Related Cancers: A Concise Outlook

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