Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma

• 成果类型: Article
• 署名作者: Krishnan, Shanmugarajan; Lee, Somin; Amoozgar, Zohreh; Subudhi, Sonu; Kumar, Ashwin Srinivasan; Posada, Jessica M.; Lindeman, Neal; Lei, Pinji; Duquette, Mark; Steinbuch, Sophie; Charabati, Marc; Huang, Peigen; Andersson, Patrik; Datta, Meenal; Munn, Lance L.; Fukumura, Dai; Jain, Rakesh K.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Massachusetts General Hospital; Harvard University; Harvard Medical School; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; Harvard University; Harvard University Medical Affiliates; Brigham & Women's Hospital; University of Bonn; Agenus Inc; Agency for Science Technology & Research (A*STAR); A*STAR - Bioprocessing Technology Institute (BTI); Rockefeller University; Cornell University; Weill Cornell Medicine; University of Notre Dame
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10968
• DOI: 10.1073/pnas.2414941122
• 发表日期: 2025-09-23
• 关键词: suppressor-cells; t-cells; tumor; cancer; expression; phenotype; survival; differentiation; maintenance; activation

摘要

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 (alpha PD1; anti-Programmed Cell Death Protein 1) in a clinically relevant, alpha PD1-resistant GBM murine model with abundant stem cells. We observed that increased levels of Wnt7b and beta-- catenin correlated with the resistance to alpha PD1. Treatment combining a porcupine inhibitor WNT974 with alpha PD1 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 alpha PD1 therapy by the expansion of antigen presenting DC3-like dendritic cells (DCs). Additionally, WNT974 combination with alpha PD1 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/beta-- catenin inhibition with alpha PD1 therapy in GBM patients with elevated Wnt7b/beta-- catenin signaling.