Shanmugarajan Krishnan, Senior Scientist of T Cell Biology at Agenus, shared a post on LinkedIn about a paper he co-authored with colleagues, published in PNAS:
“Excited to share our study from the Department of Radiation Oncology, Edwin L. Steele Laboratories, Massachusetts General Hospital, and Harvard Medical School, just published in PNAS!
Does Wnt/β-catenin signaling fuel resistance to immune checkpoint blockade in glioblastoma (GBM)? If so, how – and how can this resistance be attenuated?
To answer these questions, we leveraged stem-cell-rich, anti-PD-1–resistant GBM to judiciously test a porcupine inhibitor (WNT974) in combination with anti–PD-1.
What the combination achieved
- Remodeled the tumor immune microenvironment
- Expanded activated dendritic cells
- Reduced granulocytic MDSCs (gMDSCs)
- Increased the CD8⁺ T cell: Treg proliferative ratio and boosted CD8⁺ effector functions
- Prolonged survival in stem-cell–rich, αPD-1–resistant GBM-bearing mice
But resistance still emerged from the tumor and TME:
- Elevated mTOR and MAPK/ERK phosphorylation
- Increased monocytic MDSCs (mMDSCs)
Importantly, these resistance mechanisms were independent of tumor-intrinsic Wnt7b and stemness and consistent across anti–PD-1–resistant GBM models.
Taken together, our findings suggest that targeting the Wnt7b/β-catenin pathway could improve responsiveness to immunotherapy in select GBM patients – while also pointing to new resistance mechanisms that might guide next-generation strategies.”
Title: Wnt inhibition alleviates resistance to anti-PD1 therapy and improves antitumor immunity in glioblastoma
Authors: Shanmugarajan Krishnan, Somin Lee, Zohreh Amoozgar, Sonu Subudhi, Ashwin Srinivasan Kumar, Jessica M. Posada, Neal Lindeman, Pinji Lei, Mark Duquette, Sophie Steinbuch, Marc Charabati, Peigen Huang, Patrik Andersson, Meenal Datta, Lance L. Munn, Dai Fukumura, Rakesh K. Jain
You can read the Full Article in PNAS.
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