Dissecting the complex interplay between innate and adoptive immunity in brain metastasis for improved tumor microenvironment targeted- or immunotherapies
The development of immunotherapies has recently revolutionized treatment options for cancer patients. However, response rates vary among distinct tumor types and individual patients. Moreover, metastases often show lower response rates compared to primary tumors. The microenvironment represents a critical factor that determines disease progression and the outcome of therapeutic intervention. Given the immune-privileged status of the central nervous system (CNS), brain metastases (BrM) represent a particularly challenging entity for successful immunotherapy. We found that even though BrM induce the recruitment of myeloid and lymphoid cells into the CNS, the environment poses an immune-suppressive pressure to prevent tissue damaging inflammation. Consequently, strategies that aim to reactivate T cell function in the CNS will be blunted by immune suppressive functions of myeloid cells. Hence, immune-modulatory strategies that transiently revoke the suppressive milieu in BrM are expected to synergize with immunotherapy. The Beug Foundation Metastasis Prize will allow us to perform comprehensive analyses of the complex interplay between innate and adoptive immunity in BrM. Based on the insights from our initial analyses we will test different combination therapies in preclinical BrM models with the aim to locally block immune-suppression while promoting the effective anti-tumor responses with minimal risk to induce neurotoxic tissue damage.