Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma
Abstract
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.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (17)
Shanmugarajan Krishnan
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Somin Lee
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Zohreh Amoozgar
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Sonu Subudhi
Ashwin Srinivasan Kumar
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Jessica M. Posada
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Neal Lindeman
Department of Pathology, Brigham and Women’s Hospital
Pinji Lei
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Mark Duquette
Sophie Steinbuch
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Marc Charabati
Peigen Huang
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Patrik Andersson
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Meenal Datta
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Lance L. Munn
Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School
Dai Fukumura
Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital and Harvard Medical School
Rakesh K. Jain