The Montreal Clinical Research Institute (IRCM) is pleased to announce that an international research team led by Dr. Nabil G. Seidah (PhD, Director of the IRCM Biochemical Neuroendocrinology Research Unit and Full Professor at Université de Montréal) has made a significant breakthrough in the fight against colorectal cancer, one of the world’s deadliest cancers.
Published in a leading scientific journal, the Journal for Immunotherapy of Cancer, this study reveals that the dual inactivation of two secretory enzymes — the proprotein convertases PCSK7 and PCSK9 — can effectively eliminate liver metastases of colorectal tumours by enhancing the immune response against cancer, without observed toxicity.
A Novel Mechanism That Unlocks T Cell Potential
The research unveils a new immune-modulatory mechanism involving the non-enzymatic roles of these two convertases:
- Highly expressed in CD4+ and CD8+ T cells, PCSK7 acts as a molecular chaperone for immune checkpoint proteins (ICPs) which suppress T cell activity. Its inactivation leads to a reduction of ICP levels on T cells, leading to the efficient activation of cytotoxic T cells to effectively kill tumour cells.
- PCSK9 promotes the degradation of LDLR and MHC-I receptors. Its suppression results in a marked decrease in LDL cholesterol, and an increase in MHC-I cell surface levels, which is crucial for presenting tumour antigens to cytotoxic T cells.
- The combined inactivation of PCSK7 and PCSK9 has synergistic effects, resulting in the safe eradication of primary tumours and liver metastases without toxic side effects.
A Promising Path for Immunotherapy
This discovery could represent a turning point in cancer immunotherapy, particularly against solid metastatic tumours accounting for over 90% of all cancer-related deaths. By overcoming immune resistance through the modulation of PCSK7 and PCSK9, this strategy offers a promising, safe, and effective therapeutic pathway.
Similar results were observed in mouse models and human immune cells, making this approach highly translatable to clinical settings in the near future.
Next Steps and Future Perspectives
The team is now working on developing targeted therapies that combine PCSK9 inhibitors (already clinically approved for hypercholesterolemia) with new methods to silence PCSK7 in immune cells. Extending this strategy to other cancer types is also being explored, with the potential to greatly improve clinical practice and inform future cancer treatment protocols.
Acknowledgments
The authors wish to express their deep gratitude to all lab members and collaborators who made these findings possible, including:
Chloé Porcheron, Maïlys Le Dévéhat, Anna Roubtsova, Hadi Bayat, Alexandra Evagelidis, Vatsal Sachan, Delia Susan-Resiga, Rachid Essalmani, and Annik Prat, as well as Nathalie Labrecque (IRCM), Rebecca Crusseddu (Jean-François Côté’s laboratory, IRCM), Jean-Sébastien Delisle (Maisonneuve-Rosemont Hospital), and Abdel-Majid Khatib (University of Bordeaux).
This work was generously supported by the CIHR Foundation Grant (N.G.S.: #148363) and Operating Grant (N.G.S.: #191678), the Cancer Research Society (J-F.C.: #23545), the Canada Research Chair in Precursor Proteolysis (N.G.S.: #950-231335), Axelys/Liphorus Inc., and the CQDM via the Ministry of Economy, Innovation and Energy of Quebec (Grant N.G.S.: #SYN-366).
