Ohne Titel
Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cell...
Ausführliche Beschreibung
Gespeichert in:
| Autor*in: |
Krug, Julia [verfasserIn] Rodrian, Gabriele [verfasserIn] Petter, Katja [verfasserIn] Yang, Hai [verfasserIn] Khoziainova, Svetlana [verfasserIn] Guo, Wei [verfasserIn] Bénard, Alan [verfasserIn] Merkel, Susanne [verfasserIn] Gellert, Susan [verfasserIn] Maschauer, Simone [verfasserIn] Spermann, Monika [verfasserIn] Waldner, Maximilian [verfasserIn] Bailey, Peter [verfasserIn] Pilarsky, Christian [verfasserIn] Liebl, Andrea [verfasserIn] Tripal, Philipp [verfasserIn] Christoph, Jan [verfasserIn] Naschberger, Elisabeth [verfasserIn] Croner, Roland [verfasserIn] Schellerer, Vera S. [verfasserIn] Becker, Christoph [verfasserIn] Hartmann, Arndt [verfasserIn] Tüting, Thomas [verfasserIn] Prante, Olaf [verfasserIn] Grützmann, Robert [verfasserIn] Grivennikov, Sergei I. [verfasserIn] Stürzl, Michael [verfasserIn] Britzen-Laurent, Nathalie [verfasserIn] |
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| Format: |
E-Artikel |
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| Sprache: |
Englisch |
| Erschienen: |
2023 |
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| Schlagwörter: |
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| Übergeordnetes Werk: |
Enthalten in: Gastroenterology - Stanford, Calif. : HighWire Press, 1965, 164 |
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| Übergeordnetes Werk: |
volume:164 |
| DOI / URN: |
10.1053/j.gastro.2022.11.018 |
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| Katalog-ID: |
ELV009268227 |
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| 024 | 7 | |a 10.1053/j.gastro.2022.11.018 |2 doi | |
| 035 | |a (DE-627)ELV009268227 | ||
| 035 | |a (ELSEVIER)S0016-5085(22)01294-X | ||
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| 041 | |a eng | ||
| 082 | 0 | 4 | |a 610 |q VZ |
| 084 | |a 44.87 |2 bkl | ||
| 100 | 1 | |a Krug, Julia |e verfasserin |4 aut | |
| 264 | 1 | |c 2023 | |
| 336 | |a nicht spezifiziert |b zzz |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
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| 520 | |a Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. | ||
| 650 | 4 | |a Colon Cancer | |
| 650 | 4 | |a Immune Evasion | |
| 650 | 4 | |a IFNGR1 | |
| 700 | 1 | |a Rodrian, Gabriele |e verfasserin |4 aut | |
| 700 | 1 | |a Petter, Katja |e verfasserin |4 aut | |
| 700 | 1 | |a Yang, Hai |e verfasserin |4 aut | |
| 700 | 1 | |a Khoziainova, Svetlana |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Bénard, Alan |e verfasserin |4 aut | |
| 700 | 1 | |a Merkel, Susanne |e verfasserin |4 aut | |
| 700 | 1 | |a Gellert, Susan |e verfasserin |4 aut | |
| 700 | 1 | |a Maschauer, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Spermann, Monika |e verfasserin |4 aut | |
| 700 | 1 | |a Waldner, Maximilian |e verfasserin |4 aut | |
| 700 | 1 | |a Bailey, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Pilarsky, Christian |e verfasserin |4 aut | |
| 700 | 1 | |a Liebl, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Tripal, Philipp |e verfasserin |4 aut | |
| 700 | 1 | |a Christoph, Jan |e verfasserin |4 aut | |
| 700 | 1 | |a Naschberger, Elisabeth |e verfasserin |4 aut | |
| 700 | 1 | |a Croner, Roland |e verfasserin |4 aut | |
| 700 | 1 | |a Schellerer, Vera S. |e verfasserin |4 aut | |
| 700 | 1 | |a Becker, Christoph |e verfasserin |4 aut | |
| 700 | 1 | |a Hartmann, Arndt |e verfasserin |4 aut | |
| 700 | 1 | |a Tüting, Thomas |e verfasserin |4 aut | |
| 700 | 1 | |a Prante, Olaf |e verfasserin |4 aut | |
| 700 | 1 | |a Grützmann, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Grivennikov, Sergei I. |e verfasserin |4 aut | |
| 700 | 1 | |a Stürzl, Michael |e verfasserin |4 aut | |
| 700 | 1 | |a Britzen-Laurent, Nathalie |e verfasserin |0 (orcid)0000-0002-0494-7117 |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Gastroenterology |d Stanford, Calif. : HighWire Press, 1965 |g 164 |h Online-Ressource |w (DE-627)270937293 |w (DE-600)1478699-0 |w (DE-576)078590221 |x 1528-0012 |7 nnns |
| 773 | 1 | 8 | |g volume:164 |
| 912 | |a GBV_USEFLAG_U | ||
| 912 | |a SYSFLAG_U | ||
| 912 | |a GBV_ELV | ||
| 912 | |a SSG-OLC-PHA | ||
| 912 | |a GBV_ILN_20 | ||
| 912 | |a GBV_ILN_22 | ||
| 912 | |a GBV_ILN_23 | ||
| 912 | |a GBV_ILN_24 | ||
| 912 | |a GBV_ILN_31 | ||
| 912 | |a GBV_ILN_32 | ||
| 912 | |a GBV_ILN_39 | ||
| 912 | |a GBV_ILN_40 | ||
| 912 | |a GBV_ILN_60 | ||
| 912 | |a GBV_ILN_62 | ||
| 912 | |a GBV_ILN_63 | ||
| 912 | |a GBV_ILN_65 | ||
| 912 | |a GBV_ILN_69 | ||
| 912 | |a GBV_ILN_70 | ||
| 912 | |a GBV_ILN_73 | ||
| 912 | |a GBV_ILN_74 | ||
| 912 | |a GBV_ILN_90 | ||
| 912 | |a GBV_ILN_95 | ||
| 912 | |a GBV_ILN_100 | ||
| 912 | |a GBV_ILN_101 | ||
| 912 | |a GBV_ILN_105 | ||
| 912 | |a GBV_ILN_110 | ||
| 912 | |a GBV_ILN_151 | ||
| 912 | |a GBV_ILN_161 | ||
| 912 | |a GBV_ILN_170 | ||
| 912 | |a GBV_ILN_187 | ||
| 912 | |a GBV_ILN_206 | ||
| 912 | |a GBV_ILN_213 | ||
| 912 | |a GBV_ILN_224 | ||
| 912 | |a GBV_ILN_230 | ||
| 912 | |a GBV_ILN_285 | ||
| 912 | |a GBV_ILN_293 | ||
| 912 | |a GBV_ILN_370 | ||
| 912 | |a GBV_ILN_602 | ||
| 912 | |a GBV_ILN_702 | ||
| 912 | |a GBV_ILN_2001 | ||
| 912 | |a GBV_ILN_2003 | ||
| 912 | |a GBV_ILN_2005 | ||
| 912 | |a GBV_ILN_2007 | ||
| 912 | |a GBV_ILN_2008 | ||
| 912 | |a GBV_ILN_2009 | ||
| 912 | |a GBV_ILN_2010 | ||
| 912 | |a GBV_ILN_2011 | ||
| 912 | |a GBV_ILN_2014 | ||
| 912 | |a GBV_ILN_2015 | ||
| 912 | |a GBV_ILN_2020 | ||
| 912 | |a GBV_ILN_2021 | ||
| 912 | |a GBV_ILN_2025 | ||
| 912 | |a GBV_ILN_2026 | ||
| 912 | |a GBV_ILN_2027 | ||
| 912 | |a GBV_ILN_2034 | ||
| 912 | |a GBV_ILN_2044 | ||
| 912 | |a GBV_ILN_2048 | ||
| 912 | |a GBV_ILN_2049 | ||
| 912 | |a GBV_ILN_2050 | ||
| 912 | |a GBV_ILN_2055 | ||
| 912 | |a GBV_ILN_2056 | ||
| 912 | |a GBV_ILN_2059 | ||
| 912 | |a GBV_ILN_2061 | ||
| 912 | |a GBV_ILN_2064 | ||
| 912 | |a GBV_ILN_2088 | ||
| 912 | |a GBV_ILN_2106 | ||
| 912 | |a GBV_ILN_2110 | ||
| 912 | |a GBV_ILN_2112 | ||
| 912 | |a GBV_ILN_2122 | ||
| 912 | |a GBV_ILN_2129 | ||
| 912 | |a GBV_ILN_2143 | ||
| 912 | |a GBV_ILN_2152 | ||
| 912 | |a GBV_ILN_2153 | ||
| 912 | |a GBV_ILN_2190 | ||
| 912 | |a GBV_ILN_2232 | ||
| 912 | |a GBV_ILN_2336 | ||
| 912 | |a GBV_ILN_2470 | ||
| 912 | |a GBV_ILN_2507 | ||
| 912 | |a GBV_ILN_4012 | ||
| 912 | |a GBV_ILN_4035 | ||
| 912 | |a GBV_ILN_4037 | ||
| 912 | |a GBV_ILN_4112 | ||
| 912 | |a GBV_ILN_4125 | ||
| 912 | |a GBV_ILN_4126 | ||
| 912 | |a GBV_ILN_4242 | ||
| 912 | |a GBV_ILN_4249 | ||
| 912 | |a GBV_ILN_4251 | ||
| 912 | |a GBV_ILN_4305 | ||
| 912 | |a GBV_ILN_4306 | ||
| 912 | |a GBV_ILN_4307 | ||
| 912 | |a GBV_ILN_4313 | ||
| 912 | |a GBV_ILN_4322 | ||
| 912 | |a GBV_ILN_4323 | ||
| 912 | |a GBV_ILN_4324 | ||
| 912 | |a GBV_ILN_4325 | ||
| 912 | |a GBV_ILN_4326 | ||
| 912 | |a GBV_ILN_4333 | ||
| 912 | |a GBV_ILN_4334 | ||
| 912 | |a GBV_ILN_4338 | ||
| 912 | |a GBV_ILN_4367 | ||
| 912 | |a GBV_ILN_4393 | ||
| 912 | |a GBV_ILN_4700 | ||
| 936 | b | k | |a 44.87 |j Gastroenterologie |q VZ |
| 951 | |a AR | ||
| 952 | |d 164 | ||
| author_variant |
j k jk g r gr k p kp h y hy s k sk w g wg a b ab s m sm s g sg s m sm m s ms m w mw p b pb c p cp a l al p t pt j c jc e n en r c rc v s s vs vss c b cb a h ah t t tt o p op r g rg s i g si sig m s ms n b l nbl |
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article:15280012:2023----:: |
| hierarchy_sort_str |
2023 |
| bklnumber |
44.87 |
| publishDate |
2023 |
| allfields |
10.1053/j.gastro.2022.11.018 doi (DE-627)ELV009268227 (ELSEVIER)S0016-5085(22)01294-X DE-627 ger DE-627 rda eng 610 VZ 44.87 bkl Krug, Julia verfasserin aut 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. Colon Cancer Immune Evasion IFNGR1 Rodrian, Gabriele verfasserin aut Petter, Katja verfasserin aut Yang, Hai verfasserin aut Khoziainova, Svetlana verfasserin aut Guo, Wei verfasserin aut Bénard, Alan verfasserin aut Merkel, Susanne verfasserin aut Gellert, Susan verfasserin aut Maschauer, Simone verfasserin aut Spermann, Monika verfasserin aut Waldner, Maximilian verfasserin aut Bailey, Peter verfasserin aut Pilarsky, Christian verfasserin aut Liebl, Andrea verfasserin aut Tripal, Philipp verfasserin aut Christoph, Jan verfasserin aut Naschberger, Elisabeth verfasserin aut Croner, Roland verfasserin aut Schellerer, Vera S. verfasserin aut Becker, Christoph verfasserin aut Hartmann, Arndt verfasserin aut Tüting, Thomas verfasserin aut Prante, Olaf verfasserin aut Grützmann, Robert verfasserin aut Grivennikov, Sergei I. verfasserin aut Stürzl, Michael verfasserin aut Britzen-Laurent, Nathalie verfasserin (orcid)0000-0002-0494-7117 aut Enthalten in Gastroenterology Stanford, Calif. : HighWire Press, 1965 164 Online-Ressource (DE-627)270937293 (DE-600)1478699-0 (DE-576)078590221 1528-0012 nnns volume:164 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.87 Gastroenterologie VZ AR 164 |
| spelling |
10.1053/j.gastro.2022.11.018 doi (DE-627)ELV009268227 (ELSEVIER)S0016-5085(22)01294-X DE-627 ger DE-627 rda eng 610 VZ 44.87 bkl Krug, Julia verfasserin aut 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. Colon Cancer Immune Evasion IFNGR1 Rodrian, Gabriele verfasserin aut Petter, Katja verfasserin aut Yang, Hai verfasserin aut Khoziainova, Svetlana verfasserin aut Guo, Wei verfasserin aut Bénard, Alan verfasserin aut Merkel, Susanne verfasserin aut Gellert, Susan verfasserin aut Maschauer, Simone verfasserin aut Spermann, Monika verfasserin aut Waldner, Maximilian verfasserin aut Bailey, Peter verfasserin aut Pilarsky, Christian verfasserin aut Liebl, Andrea verfasserin aut Tripal, Philipp verfasserin aut Christoph, Jan verfasserin aut Naschberger, Elisabeth verfasserin aut Croner, Roland verfasserin aut Schellerer, Vera S. verfasserin aut Becker, Christoph verfasserin aut Hartmann, Arndt verfasserin aut Tüting, Thomas verfasserin aut Prante, Olaf verfasserin aut Grützmann, Robert verfasserin aut Grivennikov, Sergei I. verfasserin aut Stürzl, Michael verfasserin aut Britzen-Laurent, Nathalie verfasserin (orcid)0000-0002-0494-7117 aut Enthalten in Gastroenterology Stanford, Calif. : HighWire Press, 1965 164 Online-Ressource (DE-627)270937293 (DE-600)1478699-0 (DE-576)078590221 1528-0012 nnns volume:164 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.87 Gastroenterologie VZ AR 164 |
| allfields_unstemmed |
10.1053/j.gastro.2022.11.018 doi (DE-627)ELV009268227 (ELSEVIER)S0016-5085(22)01294-X DE-627 ger DE-627 rda eng 610 VZ 44.87 bkl Krug, Julia verfasserin aut 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. Colon Cancer Immune Evasion IFNGR1 Rodrian, Gabriele verfasserin aut Petter, Katja verfasserin aut Yang, Hai verfasserin aut Khoziainova, Svetlana verfasserin aut Guo, Wei verfasserin aut Bénard, Alan verfasserin aut Merkel, Susanne verfasserin aut Gellert, Susan verfasserin aut Maschauer, Simone verfasserin aut Spermann, Monika verfasserin aut Waldner, Maximilian verfasserin aut Bailey, Peter verfasserin aut Pilarsky, Christian verfasserin aut Liebl, Andrea verfasserin aut Tripal, Philipp verfasserin aut Christoph, Jan verfasserin aut Naschberger, Elisabeth verfasserin aut Croner, Roland verfasserin aut Schellerer, Vera S. verfasserin aut Becker, Christoph verfasserin aut Hartmann, Arndt verfasserin aut Tüting, Thomas verfasserin aut Prante, Olaf verfasserin aut Grützmann, Robert verfasserin aut Grivennikov, Sergei I. verfasserin aut Stürzl, Michael verfasserin aut Britzen-Laurent, Nathalie verfasserin (orcid)0000-0002-0494-7117 aut Enthalten in Gastroenterology Stanford, Calif. : HighWire Press, 1965 164 Online-Ressource (DE-627)270937293 (DE-600)1478699-0 (DE-576)078590221 1528-0012 nnns volume:164 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.87 Gastroenterologie VZ AR 164 |
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10.1053/j.gastro.2022.11.018 doi (DE-627)ELV009268227 (ELSEVIER)S0016-5085(22)01294-X DE-627 ger DE-627 rda eng 610 VZ 44.87 bkl Krug, Julia verfasserin aut 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. Colon Cancer Immune Evasion IFNGR1 Rodrian, Gabriele verfasserin aut Petter, Katja verfasserin aut Yang, Hai verfasserin aut Khoziainova, Svetlana verfasserin aut Guo, Wei verfasserin aut Bénard, Alan verfasserin aut Merkel, Susanne verfasserin aut Gellert, Susan verfasserin aut Maschauer, Simone verfasserin aut Spermann, Monika verfasserin aut Waldner, Maximilian verfasserin aut Bailey, Peter verfasserin aut Pilarsky, Christian verfasserin aut Liebl, Andrea verfasserin aut Tripal, Philipp verfasserin aut Christoph, Jan verfasserin aut Naschberger, Elisabeth verfasserin aut Croner, Roland verfasserin aut Schellerer, Vera S. verfasserin aut Becker, Christoph verfasserin aut Hartmann, Arndt verfasserin aut Tüting, Thomas verfasserin aut Prante, Olaf verfasserin aut Grützmann, Robert verfasserin aut Grivennikov, Sergei I. verfasserin aut Stürzl, Michael verfasserin aut Britzen-Laurent, Nathalie verfasserin (orcid)0000-0002-0494-7117 aut Enthalten in Gastroenterology Stanford, Calif. : HighWire Press, 1965 164 Online-Ressource (DE-627)270937293 (DE-600)1478699-0 (DE-576)078590221 1528-0012 nnns volume:164 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.87 Gastroenterologie VZ AR 164 |
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10.1053/j.gastro.2022.11.018 doi (DE-627)ELV009268227 (ELSEVIER)S0016-5085(22)01294-X DE-627 ger DE-627 rda eng 610 VZ 44.87 bkl Krug, Julia verfasserin aut 2023 nicht spezifiziert zzz rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. Colon Cancer Immune Evasion IFNGR1 Rodrian, Gabriele verfasserin aut Petter, Katja verfasserin aut Yang, Hai verfasserin aut Khoziainova, Svetlana verfasserin aut Guo, Wei verfasserin aut Bénard, Alan verfasserin aut Merkel, Susanne verfasserin aut Gellert, Susan verfasserin aut Maschauer, Simone verfasserin aut Spermann, Monika verfasserin aut Waldner, Maximilian verfasserin aut Bailey, Peter verfasserin aut Pilarsky, Christian verfasserin aut Liebl, Andrea verfasserin aut Tripal, Philipp verfasserin aut Christoph, Jan verfasserin aut Naschberger, Elisabeth verfasserin aut Croner, Roland verfasserin aut Schellerer, Vera S. verfasserin aut Becker, Christoph verfasserin aut Hartmann, Arndt verfasserin aut Tüting, Thomas verfasserin aut Prante, Olaf verfasserin aut Grützmann, Robert verfasserin aut Grivennikov, Sergei I. verfasserin aut Stürzl, Michael verfasserin aut Britzen-Laurent, Nathalie verfasserin (orcid)0000-0002-0494-7117 aut Enthalten in Gastroenterology Stanford, Calif. : HighWire Press, 1965 164 Online-Ressource (DE-627)270937293 (DE-600)1478699-0 (DE-576)078590221 1528-0012 nnns volume:164 GBV_USEFLAG_U SYSFLAG_U GBV_ELV SSG-OLC-PHA GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_32 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_70 GBV_ILN_73 GBV_ILN_74 GBV_ILN_90 GBV_ILN_95 GBV_ILN_100 GBV_ILN_101 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_187 GBV_ILN_206 GBV_ILN_213 GBV_ILN_224 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_370 GBV_ILN_602 GBV_ILN_702 GBV_ILN_2001 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2007 GBV_ILN_2008 GBV_ILN_2009 GBV_ILN_2010 GBV_ILN_2011 GBV_ILN_2014 GBV_ILN_2015 GBV_ILN_2020 GBV_ILN_2021 GBV_ILN_2025 GBV_ILN_2026 GBV_ILN_2027 GBV_ILN_2034 GBV_ILN_2044 GBV_ILN_2048 GBV_ILN_2049 GBV_ILN_2050 GBV_ILN_2055 GBV_ILN_2056 GBV_ILN_2059 GBV_ILN_2061 GBV_ILN_2064 GBV_ILN_2088 GBV_ILN_2106 GBV_ILN_2110 GBV_ILN_2112 GBV_ILN_2122 GBV_ILN_2129 GBV_ILN_2143 GBV_ILN_2152 GBV_ILN_2153 GBV_ILN_2190 GBV_ILN_2232 GBV_ILN_2336 GBV_ILN_2470 GBV_ILN_2507 GBV_ILN_4012 GBV_ILN_4035 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4242 GBV_ILN_4249 GBV_ILN_4251 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4326 GBV_ILN_4333 GBV_ILN_4334 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4393 GBV_ILN_4700 44.87 Gastroenterologie VZ AR 164 |
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Krug, Julia @@aut@@ Rodrian, Gabriele @@aut@@ Petter, Katja @@aut@@ Yang, Hai @@aut@@ Khoziainova, Svetlana @@aut@@ Guo, Wei @@aut@@ Bénard, Alan @@aut@@ Merkel, Susanne @@aut@@ Gellert, Susan @@aut@@ Maschauer, Simone @@aut@@ Spermann, Monika @@aut@@ Waldner, Maximilian @@aut@@ Bailey, Peter @@aut@@ Pilarsky, Christian @@aut@@ Liebl, Andrea @@aut@@ Tripal, Philipp @@aut@@ Christoph, Jan @@aut@@ Naschberger, Elisabeth @@aut@@ Croner, Roland @@aut@@ Schellerer, Vera S. @@aut@@ Becker, Christoph @@aut@@ Hartmann, Arndt @@aut@@ Tüting, Thomas @@aut@@ Prante, Olaf @@aut@@ Grützmann, Robert @@aut@@ Grivennikov, Sergei I. @@aut@@ Stürzl, Michael @@aut@@ Britzen-Laurent, Nathalie @@aut@@ |
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Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. 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Krug, Julia |
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610 VZ 44.87 bkl Colon Cancer Immune Evasion IFNGR1 |
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Krug, Julia Rodrian, Gabriele Petter, Katja Yang, Hai Khoziainova, Svetlana Guo, Wei Bénard, Alan Merkel, Susanne Gellert, Susan Maschauer, Simone Spermann, Monika Waldner, Maximilian Bailey, Peter Pilarsky, Christian Liebl, Andrea Tripal, Philipp Christoph, Jan Naschberger, Elisabeth Croner, Roland Schellerer, Vera S. Becker, Christoph Hartmann, Arndt Tüting, Thomas Prante, Olaf Grützmann, Robert Grivennikov, Sergei I. Stürzl, Michael Britzen-Laurent, Nathalie |
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Krug, Julia |
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10.1053/j.gastro.2022.11.018 |
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| abstract |
Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. |
| abstractGer |
Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. |
| abstract_unstemmed |
Background & Aims: Advanced colorectal carcinoma (CRC) is characterized by a high frequency of primary immune evasion and refractoriness to immunotherapy. Given the importance of interferon (IFN)-γ in CRC immunosurveillance, we investigated whether and how acquired IFN-γ resistance in tumor cells would promote tumor growth, and whether IFN-γ sensitivity could be restored.Methods: Spontaneous and colitis-associated CRC development was induced in mice with a specific IFN-γ pathway inhibition in intestinal epithelial cells. The influence of IFN-γ pathway gene status and expression on survival was assessed in patients with CRC. The mechanisms underlying IFN-γ resistance were investigated in CRC cell lines.Results: The conditional knockout of the IFN-γ receptor in intestinal epithelial cells enhanced spontaneous and colitis-associated colon tumorigenesis in mice, and the loss of IFN-γ receptor α (IFNγRα) expression by tumor cells predicted poor prognosis in patients with CRC. IFNγRα expression was repressed in human CRC cells through changes in N-glycosylation, which decreased protein stability via proteasome-dependent degradation, inhibiting IFNγR-signaling. Downregulation of the bisecting N-acetylglucosaminyltransferase III (MGAT3) expression was associated with IFN-γ resistance in all IFN-γ–resistant cells, and highly correlated with low IFNγRα expression in CRC tissues. Both ectopic and pharmacological reconstitution of MGAT3 expression with all-trans retinoic acid increased bisecting N-glycosylation, as well as IFNγRα protein stability and signaling.Conclusions: Together, our results demonstrated that tumor-associated changes in N-glycosylation destabilize IFNγRα, causing IFN-γ resistance in CRC. IFN-γ sensitivity could be reestablished through the increase in MGAT3 expression, notably via all-trans retinoic acid treatment, providing new prospects for the treatment of immune-resistant CRC. |
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Rodrian, Gabriele Petter, Katja Yang, Hai Khoziainova, Svetlana Guo, Wei Bénard, Alan Merkel, Susanne Gellert, Susan Maschauer, Simone Spermann, Monika Waldner, Maximilian Bailey, Peter Pilarsky, Christian Liebl, Andrea Tripal, Philipp Christoph, Jan Naschberger, Elisabeth Croner, Roland Schellerer, Vera S. Becker, Christoph Hartmann, Arndt Tüting, Thomas Prante, Olaf Grützmann, Robert Grivennikov, Sergei I. Stürzl, Michael Britzen-Laurent, Nathalie |
| author2Str |
Rodrian, Gabriele Petter, Katja Yang, Hai Khoziainova, Svetlana Guo, Wei Bénard, Alan Merkel, Susanne Gellert, Susan Maschauer, Simone Spermann, Monika Waldner, Maximilian Bailey, Peter Pilarsky, Christian Liebl, Andrea Tripal, Philipp Christoph, Jan Naschberger, Elisabeth Croner, Roland Schellerer, Vera S. Becker, Christoph Hartmann, Arndt Tüting, Thomas Prante, Olaf Grützmann, Robert Grivennikov, Sergei I. Stürzl, Michael Britzen-Laurent, Nathalie |
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| doi_str |
10.1053/j.gastro.2022.11.018 |
| up_date |
2024-07-06T22:34:54.258Z |
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| score |
7.399295 |