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Published on: November 28, 2015
Wnt inhibition alleviates resistance to immune checkpoint blockade in glioblastoma
Rakesh Jain1, Shanmugarajan Krishnan1, Somin Lee1
1MGH.
Abstract:
Wnt signaling plays a critical role in the progression and treatment outcome of glioblastoma (GBM). Here, we identified WNT7b as a heretofore unknown mechanism of resistance to immune checkpoint inhibition (αPD1) in GBM patients and murine models. Acquired resistance to αPD1 was found to be associated with the upregulation of Wnt7b and β-catenin protein levels in GBM in patients and in a clinically relevant, stem-rich GBM model. Combining the porcupine inhibitor WNT974 with αPD1 prolonged the survival of GBM-bearing mice. However, this combination had a dichotomous response, with a subset of tumors showing refractoriness. WNT974 and αPD1 expanded a subset of DC3-like dendritic cells (DCs) and decreased the granulocytic myeloid-derived suppressor cells (gMDSCs) in the tumor microenvironment (TME). By contrast, monocytic MDSCs (mMDSCs) increased, while T-cell infiltration remained unchanged, suggesting potential TME-mediated resistance. Our preclinical findings warrant the testing of Wnt7b/β-catenin combined with αPD1 in GBM patients with elevated Wnt7b/β-catenin signaling.
Insights
WNT7b signaling causes resistance to immune checkpoint inhibitors (αPD1) in glioblastoma (GBM). Combining WNT inhibitors with αPD1 improved survival in mice, but some tumors remained resistant, suggesting new therapeutic strategies for GBM.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Wnt signaling is crucial in glioblastoma (GBM) progression and treatment.
- Immune checkpoint inhibitors (ICIs) like αPD1 show limited efficacy in GBM.
- Mechanisms of ICI resistance in GBM require further elucidation.
Approach:
- Investigated WNT7b as a novel resistance mechanism to αPD1 in GBM.
- Utilized patient-derived GBM samples and a stem-rich murine GBM model.
- Combined a porcupine inhibitor (WNT974) with αPD1 in preclinical GBM models.
- Analyzed changes in the tumor microenvironment (TME), including immune cell populations.
Key Points:
- Upregulation of WNT7b and β-catenin correlated with acquired αPD1 resistance in GBM.
- Combination therapy of WNT974 and αPD1 prolonged survival in GBM-bearing mice.
- Treatment led to expansion of dendritic cells and decreased granulocytic myeloid-derived suppressor cells, but increased monocytic MDSCs.
- T-cell infiltration remained unchanged, indicating potential TME-mediated resistance.
Conclusions:
- WNT7b/β-catenin signaling represents a significant mechanism of αPD1 resistance in GBM.
- Combined WNT inhibition and αPD1 therapy shows promise but faces refractoriness in a subset of tumors.
- Further investigation into TME modulation is warranted for optimizing ICI therapy in GBM.
