Rakesh Jain, PhD , director of the Edwin Steele Laboratories for Tumor Biology in the Department of Radiation Oncology at Massachusetts General Hospital and Andrew Werk Professor of Radiation Oncology at Harvard Medical School, is senior and corresponding author of a new paper in PNAS, " Wnt Inhibition Alleviates Resistance to Anti-PD1 Therapy and Improves Anti-Tumor Immunity in Glioblastoma ."
Q: How would you summarize your study for a lay audience?
Brain tumor patients with glioblastoma (GBM) face extremely limited treatment options and show poor responses to current immunotherapies. New treatment strategies are desperately needed.
Wnt signaling is a crucial cell communication process that regulates various aspects of stem cell behavior. It is also pivotal in the generation of GBM and contributes to treatment resistance.
In this new study, we identify Wnt7b, which is highly expressed in GBM patients, as a previously unknown determinant of resistance to immune checkpoint blockers.
Our findings reveal that targeting the Wnt7b/β-catenin pathway can sensitize stem-cell rich GBM to immune checkpoint blockade, offering a promising new therapeutic avenue.
We also demonstrate the potential of a porcupine inhibitor, WNT974, which has been shown to be safe in a phase I trial in patients with extracranial tumors, to synergize with anti-PD1 therapy by alleviating immunosuppressive mechanisms and enhancing anti-tumor immunity.
These results support the rationale for personalized clinical trials of combination WNT974/anti-PD1 therapy in glioblastoma patients with elevated Wnt7b/β-catenin signaling, aiming to overcome resistance to immunotherapy.
Q: What question were you investigating?
Glioblastoma (GBM) is a deadly brain cancer. Current treatments, including a type of immunotherapy called anti-PD1, don't work well for most patients. We are trying to figure out why—and how to fix it.
Q: What methods or approach did you use?
We found that a molecule called Wnt7b is very active in GBM tumors. This molecule seems to help cancer suppress the immune system, making treatments like anti-PD1 less effective.
We tested a drug called WNT974, which blocks Wnt signaling, as a combination therapy along with anti-PD1 immune checkpoint therapy.
Q: What did you find?
When we gave this drug to mouse models of GBM alongside anti-PD1 therapy, the results were promising—the tumors shrank, the mice lived longer, and some mice did not develop tumors again.
A closer look revealed that the combination therapy was effective in:
- Waking up the immune system by helping special cells (called dendritic cells) make the tumor more visible
- Boosting killer T cells that attack the tumor
- Reducing suppressor cells that normally protect the tumor from immune attack
Q: What are the implications?
GBM patients face extremely limited treatment options and poor responses to current immunotherapies. Our findings reveal that targeting the Wnt7b/β-catenin pathway can sensitize stem-cell rich GBM to immune checkpoint blockade, offering a promising new therapeutic avenue.
Q: What are the next steps?
These results support the rationale for personalized clinical trials in glioblastoma patients with elevated Wnt7b/β-catenin signaling, aiming to overcome resistance to immunotherapy.
Read the paper (opens external link in new tab)
Authorship: In addition to Jain, Mass General Brigham authors include 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 and Dai Fukumura.
Paper cited: Krishnan, S., et al. "Wnt inhibition alleviates resistance to anti-PD1 therapy and improves anti-tumor immunity in glioblastoma." PNAS. DOI: https://doi.org/10.1073/pnas.2414941122
Funding: This work was supported by grants from the National Institutes of Health and the National Foundation for Cancer Research, Jane's Trust Foundation, Niles Albright Research Foundation and Harvard Ludwig Cancer Center, as well as Massachusetts General Hospital.
Disclosures: RKJ 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. LLM receives equity from Bayer and is a consultant for SimBiosys. No funding or reagents from these organizations were used in this study. SK is a current employee of and a holder of stock options with Agenus Inc. Other co-authors have no conflict of interest to declare.
