Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors
Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD‐1)/programmed cell death 1 ligand 1 (PD‐L1) pathway have transformed urothelial cancer (UC) therapy. The correlation between PD‐L1 expression and ICI effectiveness is uncertain, leaving the role of PD‐L1 as a predi...
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| Format: | Article |
| Language: | English |
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Wiley
2025-01-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13699 |
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| author | Anna Hernández‐Prat Alejo Rodriguez‐Vida Laura Cardona Mengjuan Qin Oriol Arpí‐Llucià Luis Soria‐Jiménez Sílvia Menendez Fabricio Gerel Quimis Miguel Galindo Edurne Arriola Marta Salido Nuria Juanpere‐Rodero Federico Rojo Aura Muntasell Joan Albanell Ana Rovira Joaquim Bellmunt |
| author_facet | Anna Hernández‐Prat Alejo Rodriguez‐Vida Laura Cardona Mengjuan Qin Oriol Arpí‐Llucià Luis Soria‐Jiménez Sílvia Menendez Fabricio Gerel Quimis Miguel Galindo Edurne Arriola Marta Salido Nuria Juanpere‐Rodero Federico Rojo Aura Muntasell Joan Albanell Ana Rovira Joaquim Bellmunt |
| author_sort | Anna Hernández‐Prat |
| collection | DOAJ |
| description | Immune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD‐1)/programmed cell death 1 ligand 1 (PD‐L1) pathway have transformed urothelial cancer (UC) therapy. The correlation between PD‐L1 expression and ICI effectiveness is uncertain, leaving the role of PD‐L1 as a predictive marker for ICI efficacy unclear. Among several ways to enhance the efficacy of ICI, trials are exploring combining ICIs with serine/threonine‐protein kinase mTOR (mTOR) inhibitors in different tumor types. The potential interaction between mTOR inhibitors and PD‐L1 expression in UC has not been well characterized. In our study, we investigated how phosphoinositide 3‐kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK‐228, everolimus and TAK‐117) affect PD‐L1 expression and function in preclinical bladder cancer cell models. TAK‐228 increased cell surface levels of glycosylated PD‐L1 in all but one of the seven cell lines, regardless of baseline levels. TAK‐228 promoted the secretion of epidermal growth factor (EGF) and interferon‐β (IFNβ), both linked to PD‐L1 protein induction. Blocking EGF and IFNβ receptors reversed the TAK‐228‐induced PD‐L1 increase. Additionally, TAK‐228 enhanced IFN‐γ‐induced PD‐L1 expression and intracellular HLA‐I levels in some cells. TAK‐228‐treated bladder cancer cells exhibited resistance to the cytotoxic effects of peripheral blood mononuclear cells (PBMCs) and cluster of differentiation 8 (CD8)+ T cells. The addition of an anti‐PD‐L1 antibody diminished this resistance in T24 cells. Increased expression of PD‐L1 under TAK‐228 exposure was confirmed in patient‐derived explants (PDEs) treated ex vivo. These preclinical findings suggest that mTOR inhibition with TAK‐228 can increase PD‐L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC. |
| format | Article |
| id | doaj-art-b250ddb7445f49a3ac0d07492a911200 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj-art-b250ddb7445f49a3ac0d07492a9112002025-01-07T14:42:32ZengWileyMolecular Oncology1574-78911878-02612025-01-0119115117210.1002/1878-0261.13699Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitorsAnna Hernández‐Prat0Alejo Rodriguez‐Vida1Laura Cardona2Mengjuan Qin3Oriol Arpí‐Llucià4Luis Soria‐Jiménez5Sílvia Menendez6Fabricio Gerel Quimis7Miguel Galindo8Edurne Arriola9Marta Salido10Nuria Juanpere‐Rodero11Federico Rojo12Aura Muntasell13Joan Albanell14Ana Rovira15Joaquim Bellmunt16Cancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainMedical Oncology Department Hospital del Mar‐CIBERONC Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainPathology Department Hospital del Mar‐CIBERONC Barcelona SpainPathology Department IIS Fundación Jimenez Diaz‐CIBERONC Madrid SpainImmunity and Infection Group IMIM (Hospital del Mar Research Institute)‐CIBERONC Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainCancer Research Programe IMIM (Hospital del Mar Research Institute) Barcelona SpainImmune checkpoint inhibitors (ICIs) targeting the programmed cell death protein 1 (PD‐1)/programmed cell death 1 ligand 1 (PD‐L1) pathway have transformed urothelial cancer (UC) therapy. The correlation between PD‐L1 expression and ICI effectiveness is uncertain, leaving the role of PD‐L1 as a predictive marker for ICI efficacy unclear. Among several ways to enhance the efficacy of ICI, trials are exploring combining ICIs with serine/threonine‐protein kinase mTOR (mTOR) inhibitors in different tumor types. The potential interaction between mTOR inhibitors and PD‐L1 expression in UC has not been well characterized. In our study, we investigated how phosphoinositide 3‐kinase (PI3K)/AKT/mTOR pathway inhibitors (TAK‐228, everolimus and TAK‐117) affect PD‐L1 expression and function in preclinical bladder cancer cell models. TAK‐228 increased cell surface levels of glycosylated PD‐L1 in all but one of the seven cell lines, regardless of baseline levels. TAK‐228 promoted the secretion of epidermal growth factor (EGF) and interferon‐β (IFNβ), both linked to PD‐L1 protein induction. Blocking EGF and IFNβ receptors reversed the TAK‐228‐induced PD‐L1 increase. Additionally, TAK‐228 enhanced IFN‐γ‐induced PD‐L1 expression and intracellular HLA‐I levels in some cells. TAK‐228‐treated bladder cancer cells exhibited resistance to the cytotoxic effects of peripheral blood mononuclear cells (PBMCs) and cluster of differentiation 8 (CD8)+ T cells. The addition of an anti‐PD‐L1 antibody diminished this resistance in T24 cells. Increased expression of PD‐L1 under TAK‐228 exposure was confirmed in patient‐derived explants (PDEs) treated ex vivo. These preclinical findings suggest that mTOR inhibition with TAK‐228 can increase PD‐L1 levels, potentially impacting the specific immune response against UC cells. This highlights the rationale for exploring the combination of mTOR inhibitors with ICIs in patients with advanced UC.https://doi.org/10.1002/1878-0261.13699bladder cancerHLA‐ImTORPD‐L1tumor microenvironment |
| spellingShingle | Anna Hernández‐Prat Alejo Rodriguez‐Vida Laura Cardona Mengjuan Qin Oriol Arpí‐Llucià Luis Soria‐Jiménez Sílvia Menendez Fabricio Gerel Quimis Miguel Galindo Edurne Arriola Marta Salido Nuria Juanpere‐Rodero Federico Rojo Aura Muntasell Joan Albanell Ana Rovira Joaquim Bellmunt Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors Molecular Oncology bladder cancer HLA‐I mTOR PD‐L1 tumor microenvironment |
| title | Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors |
| title_full | Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors |
| title_fullStr | Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors |
| title_full_unstemmed | Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors |
| title_short | Enhancing immunotherapy through PD‐L1 upregulation: the promising combination of anti‐PD‐L1 plus mTOR inhibitors |
| title_sort | enhancing immunotherapy through pd l1 upregulation the promising combination of anti pd l1 plus mtor inhibitors |
| topic | bladder cancer HLA‐I mTOR PD‐L1 tumor microenvironment |
| url | https://doi.org/10.1002/1878-0261.13699 |
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