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Abstract

Cutaneous malignant melanoma is a rare, but very aggressive type of skin cancer, that frequently metastasizes to the brain. As treatment options for patients suffering from brain metastases are very limited, the diagnosis of brain metastasis is associated with a poor prognosis. However, recent preclinical and clinical findings raise hope that immunotherapeutic approaches could benefit brain metastasis patients. Intracranial anti‐tumor response to immune checkpoint inhibition (ICI) is possible but strongly depends on efficient T cell recruitment to the brain. While the brain has long been considered an immune privileged organ, recent studies have suggested that special meningeal lymphatic vessels facilitate immune surveillance of brain tissue. However, in the context of brain tumors, the mechanism of T cell recruitment to the brain, and how this is affected by ICI, is still poorly understood. To elucidate anatomical and molecular mechanisms of T cell homing to brain tumors, I established novel intravital microscopy methods that allow to track T cell and tumor cell interactions in real‐time over two weeks in two different syngeneic mouse models for melanoma brain tumors. With this, I was able to visualize the dynamics of T cell recruitment to the brain during tumor development, and I discovered a new route for circulating T cells to access brain tumors via distinct anatomical structures, namely peritumoral venous vessels (PVVs). Exploitation of PVVs for T cell homing to intracranial tumors was enhanced by ICI treatment. I could demonstrate that PVVs are the sites where circulating T cells preferably arrest and extravasate. Other structures, such as brain capillaries, intratumoral blood vessels, and parasagittal regions could be excluded as alternative T cell routes to intracranial melanoma. Moreover, at PVVs, a particularly high T cell motility and number was observed, and PPVs were characterized by high luminal expression of the endothelial intercellular adhesion molecule 1 (ICAM‐1). Indeed, a trend of mitigation of ICI‐mediated T cell infiltration and intracranial tumor growth control could be detected following functional blocking of ICAM‐1 in vivo. ICI treatment increased T cell motility in the brain, facilitating the route from the PVV to the tumor, which resulted in intracranial tumor growth inhibition. These findings describe a distinct mechanism by which cellular components of the adaptive immune system can access and control brain tumors, and potentially other brain pathologies. The molecular and cellular features of PVVs, and also the specific effects of ICIs on T cell functionality in the brain in vivo, which is described for the first time, provide a fundament which will help to further improve immunotherapies against brain tumors.