Visualization in microscopy of lymphocytes (and vert) sneaking through a tumor HEV vessel (in red) during treatment with anti-PD-1 plus anti-CTLA-4 immunotherapy. The white arrow indicates a lymphocyte leaving the bloodstream and entering the tumor (in black). © Elisabeth BELLARD and Jean-Philippe GIRARD – IPBS (CNRS/UT3 Paul Sabatier)
Immunotherapy, a therapeutic strategy aimed at increasing the activity of the immune system to recognize and destroy cancer cells, has revolutionized cancer treatment over the past decade. A better understanding of how this therapeutic approach works, and in particular how killer lymphocytes access tumors during immunotherapy, could improve the effectiveness of treatments. The team of Jean-Philippe Girard, Inserm research director at the Institute of Pharmacology and Structural Biology (CNRS/Toulouse III University – Paul Sabatier), in collaboration with Gustave Roussy, has just discovered the essential role in this process of particular blood vessels, called tumor-associated HEV vessels. Scientists have succeeded in filming for the first time the lymphocytes sneaking through the wall of HEV vessels to enter tumors. In addition, researchers have shown in animal models that increasing the proportion of HEV vessels in a tumor improves the efficacy of immunotherapy and leads to tumor elimination. Finally, they found that the The probability of recovery in patients with metastatic melanoma (skin cancer) treated with immunotherapy is increased when a large number of HEV vessels are present in the tumours. The results of this study are published in the journal Cancer Cell from February 3, 2022[1].
Immunotherapy with therapeutic antibodies represents a real revolution for the treatment of cancer. It allows in particular to cure certain patients suffering from metastatic melanoma (cancer of the skin), which formerly were condemned. Unfortunately, immunotherapy does not work for all patients or for all cancers. A better understanding of the mode of action of the treatment could make it possible to improve it and make it effective in a greater number of patients.
“Killer lymphocytes”, white blood cells present in the blood, are able to eliminate cancer cells. It is essential that a large number of these killer cells can access tumors in order to defend the organism against cancer. The Toulouse team lifts the veil on the mechanisms that allow killer lymphocytes to penetrate tumors to destroy them, either spontaneously or following treatment by immunotherapy with anti-PD-1 plus anti-CTLA-4 antibodies.
Scientists have discovered that HEV vessels – for High Endothelial Veinule – very specific blood vessels are the major entry point for lymphocytes into tumours. Using sophisticated microscopy techniques, the researchers were able to film the passage of lymphocytes from the blood to the tumor in animal models. For the first time, they were thus able to visualize live and in real time the lymphocytes in the process of sneaking through the wall of the HEV vessels in order to access the cancer cells present in the tumour. “We thought that HEV vessels played an important role for lymphocyte entry into the tumor, but we were surprised to find that they were the almost exclusive entry point,” underlines Jean-Philippe Girard, Inserm research director, last author of the study.
The researchers then observed in their models that the presence of a large number of killer lymphocytes in tumors is associated with the presence of a large number of HEV vessels. In addition, they provided proof of concept that increasing the proportion of HEV vessels in a tumor improves the efficacy of anti-PD-1 plus anti-CTLA-4 immunotherapy and leads to tumor elimination.
Finally, in collaboration with Caroline Robert’s team at Gustave Roussy[2], the scientists were interested in patients with metastatic melanoma. They found that the presence of a large number of HEV vessels in tumors is associated with a better response to anti-PD-1 plus anti-CTLA-4 immunotherapy.
Labeling of HEV vessels (in brown) on a tumor section from a patient with metastatic melanoma treated with immunotherapy. © Jean-Philippe GIRARD – IPBS (CNRS/UT3 Paul Sabatier)
The next step for researchers will be to develop treatments aimed at increasing the proportion of HEV vessels in tumors, in order to improve the efficacy of immunotherapy, by enabling massive recruitment of killer lymphocytes to eradicate cancer cells. “Our work could lead to longer-term improvements in immunotherapy treatment for patients with metastatic melanoma and other types of solid tumors. They also have prognostic implications, as clinicians can now look at HEV vessels to predict a patient’s response to immunotherapy.” concludes Jean-Philippe Girard.
[1] This study was funded by Fondation ARC, FRM, INCa, ANR and Labex TOUCAN
[2] And also team leader within the Inserm U981 unit