Foto: Andreas Reeg, mail@andreasreeg.com, +49 171 544 92 47, www.andreasreeg.com
Foto: Andreas Reeg, mail@andreasreeg.com, +49 171 544 92 47, www.andreasreeg.com

Dr. Lisa Sevenich

Microenvironmental regulation of brain metastasis

Brain metastasis represent an unmet clinical issue in high demand for improved treatment options to overcome tissue-specific limitation of treatment success. Paucity in treatment success can at least in part be attributed to the highly unique tumor immune microenvironment in brain metastasis. Formation of brain metastases within the immune privileged brain parenchyma leads to recruitment of distinct lymphoid and myeloid populations derived from the bone marrow as well as border-associated areas of the central nervous system such as the meninges. Recruited immune cells together with brain resident cells form the complex tumor immune microenvironment in brain metastasis. We utilize experimental in vivo and ex vivo models as well as patient samples to gain detailed knowledge into the cellular and functional heterogeneity of different immune cell populations. We seek to identify cellular and molecular drivers of disease progression and therapy response to provide scientific rationale for the development of innovative immune-targeted therapies.

Tumor-associated macrophages and microglia in brain metastasis

Tumor-associated macrophages and microglia (TAMs) represent the most abundant immune cell type in brain metastasis. Analysis of the heterogeneous TAM population revealed functional dichotomy with brain-resident microglia being associated with house-keeping functions and host defense whereas monocyte-derived macrophages are associated with wound repair mechanisms and immune suppression. We seek to define strategies to modulate the recruitment of peripheral macrophage populations, prevent the induction of tumor-instructed phenotypes or specifically target disease-associated phenotypes.

Tumor-infiltrating T cells in brain metastasis

Brain metastasis induce infiltration of T lymphocytes. However, the majority of T cells show exhaustion phenotypes and are functionally impaired. We seek to define strategies to reactivate anti-cancer immunity using T cell directed immunotherapy in combination with radiotherapy. We utilize experimental brain metastasis models to optimize treatment schedules for radio-immunotherapy with a focus on immune modulatory effects of whole brain radiotherapy and stereotactic radiosurgery.

Perspectives for immune-targeted therapies

Myeloid- and T cell-targeted therapies show anti-cancer activity in brain metastasis models. However, adaptive resistance mechanisms blunt long-term efficacy. We seek to identify molecular switches that can be used to locally convert the immune suppressive milieu in brain metastasis into an immunogenic environment that supports anti-cancer immunity. We identified metabolic checkpoints as critical modulators of the immune status in brain metastasis. Targeting metabolic checkpoints in combination with radiotherapy results in local immune modulation that lifts the immune suppressive pressure of the myeloid compartment together T cell reactivation.

Our long-term goal is to translate our pre-clinical findings into improved treatment options for brain cancer patients.

 

Figure 1: The tumor immune microenvironment in brain metastasis comprises brain resident as well as recruited immune populations derived the bone marrow as well as border-associated region of the central nervous system.

Figure 2: Anti-cancer immunity depends on the immune status in brain metastasis. Strategies that convert immune suppressive milieus into immunogenic environments are needed to improve immunotherapies in brain metastasis.