Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles
Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central t...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2025-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15384047.2025.2455722 |
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| author | Paola A. Castagnino Derick A. Haas Luca Musante Nathalia A. Tancler Bach V. Tran Rhonda Kean Alexandra R. Steck Luis A. Martinez Elahe A. Mostaghel D. Craig Hooper Felix J. Kim |
| author_facet | Paola A. Castagnino Derick A. Haas Luca Musante Nathalia A. Tancler Bach V. Tran Rhonda Kean Alexandra R. Steck Luis A. Martinez Elahe A. Mostaghel D. Craig Hooper Felix J. Kim |
| author_sort | Paola A. Castagnino |
| collection | DOAJ |
| description | Adaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune checkpoint molecule that binds PD-1 on activated T-cells and blocks anti-tumor immunity. PD-L1 can also be incorporated into cancer cell-derived extracellular vesicles (EVs), and EV-associated PD-L1 can inactivate T-cells within the tumor microenvironment. Here, we demonstrate that a selective small molecule inhibitor of Sigma1 can block IFN-γ mediated adaptive immune resistance in part by altering the incorporation of PD-L1 into cancer cell-derived EVs. Sigma1 inhibition blocked post-translational maturation of PD-L1 downstream of IFN-γ/STAT1 signaling. Subsequently, EVs released in response to IFN-γ stimulation were significantly less potent suppressors of T-cell activation. These results suggest that by reducing tumor derived immune suppressive EVs, Sigma1 inhibition may promote antitumor immunity. Sigma1 modulation presents a novel approach to regulating the tumor immune microenvironment by altering the content and production of EVs. Altogether, these data support the notion that Sigma1 may play a role in adaptive immune resistance in the tumor microenvironment. |
| format | Article |
| id | doaj-art-8832905008ce442da750937524b30c74 |
| institution | Kabale University |
| issn | 1538-4047 1555-8576 |
| language | English |
| publishDate | 2025-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj-art-8832905008ce442da750937524b30c742025-01-26T14:05:16ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762025-12-0126110.1080/15384047.2025.2455722Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesiclesPaola A. Castagnino0Derick A. Haas1Luca Musante2Nathalia A. Tancler3Bach V. Tran4Rhonda Kean5Alexandra R. Steck6Luis A. Martinez7Elahe A. Mostaghel8D. Craig Hooper9Felix J. Kim10Department of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USAUniversity of Pennsylvania School of Veterinary Medicine, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USAGeriatric Research, Education and Clinical Center, U.S. Department of Veterans Affairs Puget Sound Health Care System, Seattle, WA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USADepartment of Pharmacology, Physiology, and Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USAAdaptive immune resistance in cancer describes the various mechanisms by which tumors adapt to evade anti-tumor immune responses. IFN-γ induction of programmed death-ligand 1 (PD-L1) was the first defined and validated adaptive immune resistance mechanism. The endoplasmic reticulum (ER) is central to adaptive immune resistance as immune modulatory secreted and integral membrane proteins are dependent on ER. Sigma1 is a unique ligand-regulated integral membrane scaffolding protein enriched in the ER of cancer cells. PD-L1 is an integral membrane glycoprotein that is translated into the ER and processed through the cellular secretory pathway. At the cell surface, PD-L1 is an immune checkpoint molecule that binds PD-1 on activated T-cells and blocks anti-tumor immunity. PD-L1 can also be incorporated into cancer cell-derived extracellular vesicles (EVs), and EV-associated PD-L1 can inactivate T-cells within the tumor microenvironment. Here, we demonstrate that a selective small molecule inhibitor of Sigma1 can block IFN-γ mediated adaptive immune resistance in part by altering the incorporation of PD-L1 into cancer cell-derived EVs. Sigma1 inhibition blocked post-translational maturation of PD-L1 downstream of IFN-γ/STAT1 signaling. Subsequently, EVs released in response to IFN-γ stimulation were significantly less potent suppressors of T-cell activation. These results suggest that by reducing tumor derived immune suppressive EVs, Sigma1 inhibition may promote antitumor immunity. Sigma1 modulation presents a novel approach to regulating the tumor immune microenvironment by altering the content and production of EVs. Altogether, these data support the notion that Sigma1 may play a role in adaptive immune resistance in the tumor microenvironment.https://www.tandfonline.com/doi/10.1080/15384047.2025.2455722Sigma1/SIGMAR1extracellular vesicle (EV)programmed death ligand 1 (PD-L1)EV-associated PD-L1 (evPD-L1)Interferon-gamma (ifn-γ)adaptive immune resistance (AIR) |
| spellingShingle | Paola A. Castagnino Derick A. Haas Luca Musante Nathalia A. Tancler Bach V. Tran Rhonda Kean Alexandra R. Steck Luis A. Martinez Elahe A. Mostaghel D. Craig Hooper Felix J. Kim Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles Cancer Biology & Therapy Sigma1/SIGMAR1 extracellular vesicle (EV) programmed death ligand 1 (PD-L1) EV-associated PD-L1 (evPD-L1) Interferon-gamma (ifn-γ) adaptive immune resistance (AIR) |
| title | Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles |
| title_full | Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles |
| title_fullStr | Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles |
| title_full_unstemmed | Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles |
| title_short | Sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles |
| title_sort | sigma1 inhibitor suppression of adaptive immune resistance mechanisms mediated by cancer cell derived extracellular vesicles |
| topic | Sigma1/SIGMAR1 extracellular vesicle (EV) programmed death ligand 1 (PD-L1) EV-associated PD-L1 (evPD-L1) Interferon-gamma (ifn-γ) adaptive immune resistance (AIR) |
| url | https://www.tandfonline.com/doi/10.1080/15384047.2025.2455722 |
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