Targeting and customizing blood vessels in tumors to increase T cell infiltration and maintain their function may represent the next breakthrough in cancer therapy. The European Research Council has recognized this by awarding a prestigious Synergy Grant to the project VASC-IMMUNE, where three researchers, each possessing complementary expertise in this research topic, will synergize to advance the field. Professors Anna Dimberg and Magnus Essand are both from the Department of Immunology, Genetics and Pathology, Uppsala University and Professor Thomas Tüting is from the Department of Dermatology, University Hospital Magdeburg.
The successful implementation of immunotherapy over the last 10 years represents a true paradigm shift in cancer treatment. We know today that tumor-reactive T cells inside tumors can be made more potent through immune checkpoint blockade (e.g., anti-PD1 antibodies). These special medications release the 'brakes' of the immune system that prevent T cells from attacking the tumor and can therefore significantly improve the chances of survival for many cancer patients. We also know that immune checkpoint inhibitors tend not to work when T cells are absent in tumor tissues. Since T cells enter tumor tissues from the circulation, the tumor vasculature plays an important role in their recruitment. In this process, endothelial cells that form the vasculature interact in a reciprocal manner with immune cells. Together, they shape the composition and function of the vascular and immune landscapes in tumor tissues. However, the underlying molecular mechanisms are incompletely understood.
The VASC-IMMUNE project addresses the interaction between endothelial and immune cells focusing on both melanoma, a malignant skin cancer where many patients benefit from immunotherapies, and glioblastoma, a malignant brain cancer where current immunotherapies so far have not been able to improve patient survival.
We will utilize the fact that in melanoma some patients respond very well to immunotherapy, while others do not."
Professor Thomas Tüting, Department of Dermatology, University Hospital Magdeburg
He continues, "we know that responders tend to have higher numbers of T cells in their tumor tissues. Many T cells are found near specialized endothelial cells together with other immune cell types in structures called immune hubs. By connecting detailed cellular and molecular investigations of the vascular and immune landscapes in carefully selected tumor material from responding and non-responding patients, we hope to identify factors in the vascular-immune crosstalk that governs the responsiveness to immunotherapies."
"I have been studying glioblastoma vessels and their interaction with immune cells for many years", says Anna Dimberg. "I am confident that comparing detailed comparison of the vascular and immune landscapes in melanoma and glioblastoma tissues will reveal transcriptional networks in endothelial cells that determine how tumor vessels interact with immune cells. Once we have learnt this, we will reprogram tumor vessel function utilizing important transcription factors that optimize the ability of endothelial cells to recruit T cells and support the formation of activating immune hubs in tumor tissues."
However, targeting and transcriptionally reprogramming tumor vessels in cancer patients possess a significant challenge. The contribution of my research groups will be to develop a novel viral vector that can specifically target tumor vessels while sparing normal blood vessels", says Magnus Essand. "We have already shown that this is possible in mouse models of glioblastoma and together, we will now translate this finding to human tumor vessels, not only in glioblastoma and melanoma but in tumor vessels in general. This is why the project has such great transformational potential."
The 6-year project will start in the first half of 2025. The researchers expect to work closely and share data, expertise and personnel to advance the project and at the same time create a rich and stimulating environment for young researchers to grow.
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