Loss of Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Tumor Microenvironment and Response to BCG Immunotherapy in a Murine Orthotopic Model of Bladder Cancer.
| Title: | Loss of Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Tumor Microenvironment and Response to BCG Immunotherapy in a Murine Orthotopic Model of Bladder Cancer. |
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| Authors: | Patwardhan, Mugdha V.1 (AUTHOR) mugdha.p@u.nus.edu, Kane, Toh Qin2 (AUTHOR) kane9530@hotmail.com, Chiong, Edmund1,3 (AUTHOR) surce@nus.edu.sg, Rahmat, Juwita Norasmara1 (AUTHOR) juwita.r@nus.edu.sg, Mahendran, Ratha1 (AUTHOR) surrm@nus.edu.sg |
| Source: | International Journal of Molecular Sciences. Dec2024, Vol. 25 Issue 24, p13296. 15p. |
| Subject Terms: | *NON-muscle invasive bladder cancer, *BCG immunotherapy, *GENE expression, *INTRAVESICAL administration, *MYCOBACTERIUM bovis |
| Abstract: | Loss of the glutathione-S-transferases Theta 2 (Gstt2) expression is associated with an improved response to intravesical Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC) patients who receive fewer BCG instillations. To delineate the cause, Gstt2 knockout (KO) and wildtype (WT) C57Bl/6J mice were implanted with tumors before treatment with BCG or saline. RNA was analyzed via single-cell RNA sequencing (scRNA-seq) and real-time polymerase chain reaction (RT-PCR). BCG induced PD-L1 expression in WT mice bladders, while pro-inflammatory TNF-α was upregulated in KO bladders. ScRNA-seq analysis showed that Gstt2 WT mice bladders had a higher proportion of matrix remodeling fibroblasts, M2 macrophages, and neuronal cells. In KO mice, distinct tumor cell types, activated fibroblasts, and M1 macrophages were enriched in the bladders. In WT bladders, the genes expressed supported tumorigenesis and immunosuppressive PD-L1 expression. In contrast, Gstt2 KO bladders expressed genes involved in inflammation, immune activation, and tumor suppression. An 11-gene signature (Hmga2, Peak 1, Kras, Slc2a1, Ankfn1, Ahnak, Cmss1, Fmo5, Gphn, Plec, Gstt2), derived from the scRNA-seq analysis predicted response in NMIBC patients (The Cancer Genome Atlas (TCGA) database). In conclusion, our results indicate that patients with WT Gstt2 may benefit from anti-PD-L1 checkpoint inhibition therapy. [ABSTRACT FROM AUTHOR] |
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| Items | – Name: Title Label: Title Group: Ti Data: Loss of Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Tumor Microenvironment and Response to BCG Immunotherapy in a Murine Orthotopic Model of Bladder Cancer. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Patwardhan%2C+Mugdha+V%2E%22">Patwardhan, Mugdha V.</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> mugdha.p@u.nus.edu</i><br /><searchLink fieldCode="AR" term="%22Kane%2C+Toh+Qin%22">Kane, Toh Qin</searchLink><relatesTo>2</relatesTo> (AUTHOR)<i> kane9530@hotmail.com</i><br /><searchLink fieldCode="AR" term="%22Chiong%2C+Edmund%22">Chiong, Edmund</searchLink><relatesTo>1,3</relatesTo> (AUTHOR)<i> surce@nus.edu.sg</i><br /><searchLink fieldCode="AR" term="%22Rahmat%2C+Juwita+Norasmara%22">Rahmat, Juwita Norasmara</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> juwita.r@nus.edu.sg</i><br /><searchLink fieldCode="AR" term="%22Mahendran%2C+Ratha%22">Mahendran, Ratha</searchLink><relatesTo>1</relatesTo> (AUTHOR)<i> surrm@nus.edu.sg</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22International+Journal+of+Molecular+Sciences%22">International Journal of Molecular Sciences</searchLink>. Dec2024, Vol. 25 Issue 24, p13296. 15p. – Name: Subject Label: Subject Terms Group: Su Data: *<searchLink fieldCode="DE" term="%22NON-muscle+invasive+bladder+cancer%22">NON-muscle invasive bladder cancer</searchLink><br />*<searchLink fieldCode="DE" term="%22BCG+immunotherapy%22">BCG immunotherapy</searchLink><br />*<searchLink fieldCode="DE" term="%22GENE+expression%22">GENE expression</searchLink><br />*<searchLink fieldCode="DE" term="%22INTRAVESICAL+administration%22">INTRAVESICAL administration</searchLink><br />*<searchLink fieldCode="DE" term="%22MYCOBACTERIUM+bovis%22">MYCOBACTERIUM bovis</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Loss of the glutathione-S-transferases Theta 2 (Gstt2) expression is associated with an improved response to intravesical Mycobacterium bovis, Bacillus Calmette-Guérin (BCG) immunotherapy for non-muscle-invasive bladder cancer (NMIBC) patients who receive fewer BCG instillations. To delineate the cause, Gstt2 knockout (KO) and wildtype (WT) C57Bl/6J mice were implanted with tumors before treatment with BCG or saline. RNA was analyzed via single-cell RNA sequencing (scRNA-seq) and real-time polymerase chain reaction (RT-PCR). BCG induced PD-L1 expression in WT mice bladders, while pro-inflammatory TNF-α was upregulated in KO bladders. ScRNA-seq analysis showed that Gstt2 WT mice bladders had a higher proportion of matrix remodeling fibroblasts, M2 macrophages, and neuronal cells. In KO mice, distinct tumor cell types, activated fibroblasts, and M1 macrophages were enriched in the bladders. In WT bladders, the genes expressed supported tumorigenesis and immunosuppressive PD-L1 expression. In contrast, Gstt2 KO bladders expressed genes involved in inflammation, immune activation, and tumor suppression. An 11-gene signature (Hmga2, Peak 1, Kras, Slc2a1, Ankfn1, Ahnak, Cmss1, Fmo5, Gphn, Plec, Gstt2), derived from the scRNA-seq analysis predicted response in NMIBC patients (The Cancer Genome Atlas (TCGA) database). In conclusion, our results indicate that patients with WT Gstt2 may benefit from anti-PD-L1 checkpoint inhibition therapy. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of International Journal of Molecular Sciences is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.3390/ijms252413296 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 15 StartPage: 13296 Subjects: – SubjectFull: NON-muscle invasive bladder cancer Type: general – SubjectFull: BCG immunotherapy Type: general – SubjectFull: GENE expression Type: general – SubjectFull: INTRAVESICAL administration Type: general – SubjectFull: MYCOBACTERIUM bovis Type: general Titles: – TitleFull: Loss of Glutathione-S-Transferase Theta 2 (GSTT2) Modulates the Tumor Microenvironment and Response to BCG Immunotherapy in a Murine Orthotopic Model of Bladder Cancer. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Patwardhan, Mugdha V. – PersonEntity: Name: NameFull: Kane, Toh Qin – PersonEntity: Name: NameFull: Chiong, Edmund – PersonEntity: Name: NameFull: Rahmat, Juwita Norasmara – PersonEntity: Name: NameFull: Mahendran, Ratha IsPartOfRelationships: – BibEntity: Dates: – D: 15 M: 12 Text: Dec2024 Type: published Y: 2024 Identifiers: – Type: issn-print Value: 16616596 Numbering: – Type: volume Value: 25 – Type: issue Value: 24 Titles: – TitleFull: International Journal of Molecular Sciences Type: main |
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