Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma.
Gespeichert in:
| Titel: | Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma. |
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| Autoren: | Krishnan S; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Lee S; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Amoozgar Z; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Subudhi S; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Srinivasan Kumar A; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.; Harvard-Massachusetts Institute of Technology, Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139., Posada JM; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115., Lindeman N; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115., Lei P; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Duquette M; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Steinbuch S; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114.; Department of Dermatology, University Medical Center Bonn, Bonn 53127, Germany., Charabati M; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Huang P; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Andersson P; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Datta M; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Munn LL; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Fukumura D; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114., Jain RK; Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114. |
| Quelle: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2025 Sep 23; Vol. 122 (38), pp. e2414941122. Date of Electronic Publication: 2025 Sep 15. |
| Publikationsart: | Journal Article |
| Sprache: | English |
| Info zur Zeitschrift: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : National Academy of Sciences |
| MeSH-Schlagworte: | Glioblastoma*/immunology , Glioblastoma*/drug therapy , Glioblastoma*/pathology , Glioblastoma*/metabolism , Glioblastoma*/genetics , Drug Resistance, Neoplasm*/drug effects , Programmed Cell Death 1 Receptor*/antagonists & inhibitors , Immune Checkpoint Inhibitors*/pharmacology , Immune Checkpoint Inhibitors*/therapeutic use , Brain Neoplasms*/immunology , Brain Neoplasms*/drug therapy , Wnt Proteins*/antagonists & inhibitors , Wnt Proteins*/metabolism , Wnt Proteins*/genetics, Animals ; Mice ; Humans ; Wnt Signaling Pathway/drug effects ; Tumor Microenvironment/drug effects ; Tumor Microenvironment/immunology ; Cell Line, Tumor ; beta Catenin/metabolism ; Female ; Pyridines ; Benzeneacetamides |
| Abstract: | Competing Interests: Competing interests statement:R.K.J. received consultant fees from SynDevRx; owns equity in Accurius, Enlight, and SynDevRx; served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund; and received research grants Sanofi. L.L.M. receives equity from Bayer and is a consultant for SimBiosys. No funding or reagents from these organizations were used in this study. S.K. is a current employee of and a holder of stock options with Agenus Inc. Other co-authors have no conflict of interest to declare. Wnt signaling plays a crucial role for many developmental processes. It is also pivotal in the generation and limited treatment outcomes of glioblastoma (GBM). Here, we identified Wnt7b, which is markedly upregulated in GBM patients, as a determinant of resistance to immune checkpoint blockers (αPD1; anti-Programmed Cell Death Protein 1) in a clinically relevant, αPD1-resistant GBM murine model with abundant stem cells. We observed that increased levels of Wnt7b and β-catenin correlated with the resistance to αPD1. Treatment combining a porcupine inhibitor WNT974 with αPD1 reprogrammed the immune suppressive tumor microenvironment (TME) to bolster antitumor immune responses and extended the survival of mice bearing orthotopic GBM, with 25% long-term survivors. Our causal studies revealed that WNT974 potentiated αPD1 therapy by the expansion of antigen presenting DC3-like dendritic cells (DCs). Additionally, WNT974 combination with αPD1 was associated with a reduction in immune suppressive granulocytic myeloid-derived suppressor cells (MDSCs), an increase in the Ki67+CD8/Ki67+regulatory T cells (Treg) ratio, tilting the CD8:Treg balance in the TME toward antitumor immune response, and more pronounced GrzB+CD8+ effector T cells. Conversely, an increase in monocytic MDSCs and phosphorylation of pro-oncogenic proteins was associated with resistance to the combination therapy. Collectively, our preclinical findings provide a strong rationale to test Wnt7b/β-catenin inhibition with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling. |
| Kommentare: | Comment in: Proc Natl Acad Sci U S A. 2025 Nov 4;122(44):e2523639122. doi: 10.1073/pnas.2523639122.. (PMID: 41144679) |
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| Grant Information: | K22 CA258410 United States CA NCI NIH HHS; R01 NS118929 United States NS NINDS NIH HHS; R21 EB031982 United States EB NIBIB NIH HHS; T32 CA251062 United States CA NCI NIH HHS; R35 CA197743 United States CA NCI NIH HHS; R01 NS100808 United States NS NINDS NIH HHS; U01 CA261842 United States CA NCI NIH HHS; R01 CA208205 United States CA NCI NIH HHS; R01 CA247441 United States CA NCI NIH HHS; W81XWH-19-1-0723 DOD | U.S. Army (USA); U01 CA224348 United States CA NCI NIH HHS; R01 MH110438 United States MH NIMH NIH HHS; R01 CA259253 United States CA NCI NIH HHS; T32 HL007627 United States HL NHLBI NIH HHS |
| Contributed Indexing: | Keywords: Wnt7b/β-catenin; dendritic cells; glioblastoma; immunotherapy; stem cells |
| Substance Nomenclature: | 0 (Programmed Cell Death 1 Receptor) 0 (Immune Checkpoint Inhibitors) 0 (Wnt Proteins) 0 (beta Catenin) 0 (2-(4-(2-methylpyridin-4-yl)phenyl)-N-(4-(pyridin-3-yl)phenyl)acetamide) 0 (Pyridines) 0 (Benzeneacetamides) |
| Entry Date(s): | Date Created: 20250915 Date Completed: 20250916 Latest Revision: 20251027 |
| Update Code: | 20251028 |
| PubMed Central ID: | PMC12478157 |
| DOI: | 10.1073/pnas.2414941122 |
| PMID: | 40953263 |
| Datenbank: | MEDLINE |
Nájsť tento článok vo Web of Science | Abstract: | Competing Interests: Competing interests statement:R.K.J. received consultant fees from SynDevRx; owns equity in Accurius, Enlight, and SynDevRx; served on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, and Tekla World Healthcare Fund; and received research grants Sanofi. L.L.M. receives equity from Bayer and is a consultant for SimBiosys. No funding or reagents from these organizations were used in this study. S.K. is a current employee of and a holder of stock options with Agenus Inc. Other co-authors have no conflict of interest to declare.<br />Wnt signaling plays a crucial role for many developmental processes. It is also pivotal in the generation and limited treatment outcomes of glioblastoma (GBM). Here, we identified Wnt7b, which is markedly upregulated in GBM patients, as a determinant of resistance to immune checkpoint blockers (αPD1; anti-Programmed Cell Death Protein 1) in a clinically relevant, αPD1-resistant GBM murine model with abundant stem cells. We observed that increased levels of Wnt7b and β-catenin correlated with the resistance to αPD1. Treatment combining a porcupine inhibitor WNT974 with αPD1 reprogrammed the immune suppressive tumor microenvironment (TME) to bolster antitumor immune responses and extended the survival of mice bearing orthotopic GBM, with 25% long-term survivors. Our causal studies revealed that WNT974 potentiated αPD1 therapy by the expansion of antigen presenting DC3-like dendritic cells (DCs). Additionally, WNT974 combination with αPD1 was associated with a reduction in immune suppressive granulocytic myeloid-derived suppressor cells (MDSCs), an increase in the Ki67+CD8/Ki67+regulatory T cells (Treg) ratio, tilting the CD8:Treg balance in the TME toward antitumor immune response, and more pronounced GrzB+CD8+ effector T cells. Conversely, an increase in monocytic MDSCs and phosphorylation of pro-oncogenic proteins was associated with resistance to the combination therapy. Collectively, our preclinical findings provide a strong rationale to test Wnt7b/β-catenin inhibition with αPD1 therapy in GBM patients with elevated Wnt7b/β-catenin signaling. |
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| ISSN: | 1091-6490 |
| DOI: | 10.1073/pnas.2414941122 |