PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors
Background The prototypical type I natural killer T (NKT) cell agonist, α-galactosylceramide (α-GalCer), has shown only minimal effects against solid tumors in the clinic. The most promising clinical application of α-GalCer currently entails ex vivo priming of patient-derived dendritic cells; howeve...
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BMJ Publishing Group
2025-03-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Online Access: | https://jitc.bmj.com/content/13/3/e009539.full |
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| author | Jay A Berzofsky Shweta Tiwary Julian Burks David M Stevens Sarah L Skoczen Ruvanthi N Kularatne Stephan T Stern |
| author_facet | Jay A Berzofsky Shweta Tiwary Julian Burks David M Stevens Sarah L Skoczen Ruvanthi N Kularatne Stephan T Stern |
| author_sort | Jay A Berzofsky |
| collection | DOAJ |
| description | Background The prototypical type I natural killer T (NKT) cell agonist, α-galactosylceramide (α-GalCer), has shown only minimal effects against solid tumors in the clinic. The most promising clinical application of α-GalCer currently entails ex vivo priming of patient-derived dendritic cells; however, this technology suffers from cost, logistical concerns, and safety issues. As a parenteral dendritic cell-targeted alternative, we demonstrate that poly(L-lysine succinylated) (PLS)-α-GalCer, a novel scavenger receptor-A1 targeted α-GalCer prodrug has enhanced antitumor activity compared with α-GalCer.Methods To compare the antitumor activity of PLS-α-GalCer and α-GalCer, we used mouse syngeneic subcutaneous pancreatic and cervical tumor models using Panc02 and TC-1 cells, respectively. Intratumoral immune cell infiltration was evaluated using flow cytometry and immunohistochemistry whole-slide scan analysis. Serum cytokine levels were examined by ELISA and LEGENDplex analysis. Type I NKT cell intracellular interferon-gamma (IFN-γ) levels were determined by flow cytometry. Immunofluorescence was used to test the uptake and processing of PLS-α-GalCer and α-GalCer in antigen-presenting cells (APCs).Results The scavenger receptor A1 (SR-A1)-mediated targeting of α-GalCer to APCs by PLS-α-GalCer significantly improves the antitumor function against solid tumors compared with α-GalCer. The Panc02 and TC-1 tumor models demonstrated that PLS-α-GalCer increases intratumoral antigen-specific T, NKT and T cells, and increases the M1/M2 macrophage ratio. In the TC-1 tumor model, we demonstrated that PLS-α-GalCer synergizes with an E7 tumor vaccine to significantly suppress tumor growth and increase the survival of mice. Furthermore, the antitumor function of PLS-α-GalCer is dependent on type I NKT cells and requires SR-A1 targeting. In addition, using SR-A1 knockout RAW cells, a murine macrophage cell line, we showed that PLS-α-GalCer uptake and processing in APCs are more efficient compared with α-GalCer. PLS-α-GalCer also induces significantly less serum Th2 and Th17 cytokines while stimulating significantly more IFN-γ for a longer period and increases Th1:Th2 cytokine ratios compared with α-GalCer.Conclusions PLS-α-GalCer is a promising immunotherapy for the treatment of solid tumors that has superior antitumor activity compared with α-GalCer and could be combined with tumor vaccines and potentially other immunotherapies such as immune checkpoint inhibitors. |
| format | Article |
| id | doaj-art-d4d36a0c983f42e3b2d088e0feeed057 |
| institution | OA Journals |
| issn | 2051-1426 |
| language | English |
| publishDate | 2025-03-01 |
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| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj-art-d4d36a0c983f42e3b2d088e0feeed0572025-08-20T01:50:06ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262025-03-0113310.1136/jitc-2024-009539PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumorsJay A Berzofsky0Shweta Tiwary1Julian Burks2David M Stevens3Sarah L Skoczen4Ruvanthi N Kularatne5Stephan T Stern6Vaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USAVaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USAVaccine Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USANanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, Maryland, USANanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, Maryland, USANanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, Maryland, USANanotechnology Characterization Laboratory, Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research Sponsored by the National Cancer Institute, Frederick, Maryland, USABackground The prototypical type I natural killer T (NKT) cell agonist, α-galactosylceramide (α-GalCer), has shown only minimal effects against solid tumors in the clinic. The most promising clinical application of α-GalCer currently entails ex vivo priming of patient-derived dendritic cells; however, this technology suffers from cost, logistical concerns, and safety issues. As a parenteral dendritic cell-targeted alternative, we demonstrate that poly(L-lysine succinylated) (PLS)-α-GalCer, a novel scavenger receptor-A1 targeted α-GalCer prodrug has enhanced antitumor activity compared with α-GalCer.Methods To compare the antitumor activity of PLS-α-GalCer and α-GalCer, we used mouse syngeneic subcutaneous pancreatic and cervical tumor models using Panc02 and TC-1 cells, respectively. Intratumoral immune cell infiltration was evaluated using flow cytometry and immunohistochemistry whole-slide scan analysis. Serum cytokine levels were examined by ELISA and LEGENDplex analysis. Type I NKT cell intracellular interferon-gamma (IFN-γ) levels were determined by flow cytometry. Immunofluorescence was used to test the uptake and processing of PLS-α-GalCer and α-GalCer in antigen-presenting cells (APCs).Results The scavenger receptor A1 (SR-A1)-mediated targeting of α-GalCer to APCs by PLS-α-GalCer significantly improves the antitumor function against solid tumors compared with α-GalCer. The Panc02 and TC-1 tumor models demonstrated that PLS-α-GalCer increases intratumoral antigen-specific T, NKT and T cells, and increases the M1/M2 macrophage ratio. In the TC-1 tumor model, we demonstrated that PLS-α-GalCer synergizes with an E7 tumor vaccine to significantly suppress tumor growth and increase the survival of mice. Furthermore, the antitumor function of PLS-α-GalCer is dependent on type I NKT cells and requires SR-A1 targeting. In addition, using SR-A1 knockout RAW cells, a murine macrophage cell line, we showed that PLS-α-GalCer uptake and processing in APCs are more efficient compared with α-GalCer. PLS-α-GalCer also induces significantly less serum Th2 and Th17 cytokines while stimulating significantly more IFN-γ for a longer period and increases Th1:Th2 cytokine ratios compared with α-GalCer.Conclusions PLS-α-GalCer is a promising immunotherapy for the treatment of solid tumors that has superior antitumor activity compared with α-GalCer and could be combined with tumor vaccines and potentially other immunotherapies such as immune checkpoint inhibitors.https://jitc.bmj.com/content/13/3/e009539.full |
| spellingShingle | Jay A Berzofsky Shweta Tiwary Julian Burks David M Stevens Sarah L Skoczen Ruvanthi N Kularatne Stephan T Stern PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors Journal for ImmunoTherapy of Cancer |
| title | PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors |
| title_full | PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors |
| title_fullStr | PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors |
| title_full_unstemmed | PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors |
| title_short | PLS-α-GalCer: a novel targeted glycolipid therapy for solid tumors |
| title_sort | pls α galcer a novel targeted glycolipid therapy for solid tumors |
| url | https://jitc.bmj.com/content/13/3/e009539.full |
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