Blood vessels fighting cancer: development of a treatment that enhances the effectiveness of immunotherapy by increasing the entry of ‘killer’ lymphocytes into tumors
Immunotherapy represents a true revolution in cancer treatment. With immunotherapy, some patients with previously incurable cancers go into remission and achieve long-term survival. Unfortunately, immunotherapy does not work for all patients or all types of cancer. It is therefore essential to improve its effectiveness.
For immunotherapy to be effective, ‘killer’ lymphocytes—a type of white blood cell—must be able to access tumors in order to destroy cancer cells. In the context of an international collaboration with Rockefeller University in New York, the team led by Jean-Philippe Girard at IPBS has just developed a treatment that targets blood vessels to enhance the effectiveness of immunotherapy.
This treatment increases the proportion of HEVs—specialized blood vessels that enable killer cells to enter tumors and eliminate cancer cells.
The results of this study are published in the June 3, 2025 issue of Cell Reports Medicine.
Diagram showing lymphocytes (in green) sneaking through the wall of a tumor HEV vessel (in red) during immunotherapy treatment. The white arrow points to a lymphocyte exiting the bloodstream and entering the tumor (in black).
©Jean-Philippe GIRARD – IPBS (CNRS/University of Toulouse)
Immunotherapy is a groundbreaking cancer treatment based on the use of antibodies targeting the PD-1 and CTLA-4 molecules. This treatment works wonders for some patients, but unfortunately, it is not effective for all patients or all types of cancer. It is therefore urgent to improve the efficacy of immunotherapy so that more patients can benefit from it.
Immunotherapy works by activating “killer lymphocytes,” white blood cells circulating in the blood that are capable of eliminating cancer cells. For immunotherapy to be effective, a large number of these killer cells must be able to reach tumors in order to destroy cancer cells. Researchers have now developed a treatment that increases the proportion of HEVs—High Endothelial Venules—unusual blood vessels that serve as entry gates for lymphocytes into tumors. The treatment is based on the use of optimized anti-CTLA-4 antibodies, in which the constant region of the antibody has been modified.
Using humanized mouse models, the researchers showed that these second-generation anti-CTLA-4 antibodies have the unique ability to increase the number of HEVs—an effect not observed with ipilimumab, the first-generation anti-CTLA-4 antibody currently used in patients. By increasing HEV formation, these optimized antibodies enable greater recruitment of killer cells into tumors and thereby improve the efficacy of immunotherapy. This effect was particularly evident in preclinical models of “cold” tumors, which are resistant to anti-PD-1 antibodies when used alone.
Thousands of patients with various types of cancer are currently being treated with immunotherapy using anti-PD-1 antibodies, either alone or in combination with first-generation anti-CTLA-4 antibodies. Ultimately, the use of optimized second-generation anti-CTLA-4 antibodies, which are currently undergoing clinical trials, could significantly enhance the effectiveness of immunotherapy, especially for patients who do not respond adequately to anti-PD-1 treatment.
Reference
Fc-optimized anti-CTLA-4 antibodies increase tumor-associated high endothelial venules and sensitize refractory tumors to PD-1 blockade
Lucas Blanchard#*, Estefania Vina#, Jerko Ljubetic, Cécile Meneur, Dorian Tarroux, Maria Baez, Alessandra Marino, Nathalie Ortega, David A. Knorr, Jeffrey V. Ravetch and Jean-Philippe Girard*. Cell Rep Med DOI : 10.1016/j.xcrm.2025.102141 #equal contribution, * corresponding authors
Contact (Scientist)
Jean-Philippe Girard | jean-philippe.girard@ipbs.fr
Contact (Press)
Communication@ipbs.fr
Financial support
This study was funded by the French League Against Cancer, the National Cancer Institute (INCa), the ARC Foundation, the Bristol Myers Squibb Foundation for Research in Immuno-Oncology, the Labex TOUCAN, and the French Foundation for Medical Research (FRM).