Optimizing systemic immunotherapy for personalized brain metastasis treatment

ABSTRACT – PROJECT 3 By definition, when patients develop brain metastasis (BM) from their systemic cancer, they become stage IV and their prognosis drops to under a year. While the mechanism behind brain-tropism of different tumors (Project 1) and the role of resident immune cells in supporting brain metastasis (Project 2) need to be elucidated, there is also a gap in our understanding of how brain tumors represent an inflection point in patient survival and anti- tumor response. We have previously observed evidence of intracranial metastases dampening the immune response mounted by cytotoxic T lymphocytes. Understanding the mechanism by which tumor-associated macrophages (TAMs) recruited to BMs exert said immunosuppression is crucial for the successful treatment of brain metastasis. We propose to study the role of TAMs in dampening T cell priming via a TGF-β mediated pathway. We hypothesize that TGF-β released by TAMs in the BM act at the level of the draining lymph nodes to induce global immunosuppression. We believe that blockade of TGF-β at the lymph nodes will augment an antitumor immune response induced by checkpoint-blockade or vaccination strategies (such as with induced pluripotent stem cells or iPSCs). To test our hypothesis, we will investigate the: i) migration of TAMs to BMs and tumor draining lymph nodes and its effects on T cell priming, ii) role of TGF-β secreted by the TAMs in mediating said immunosuppression at the level of the draining lymph nodes, and iii) synergy of inhibiting TGF-β signaling and iPSC vaccines to treat BMs. We expect that the data generated from these studies will provide novel insights into a previously unexplored mechanism by which BM-infiltrating TAMs exert systemic immunosuppression and open new avenues for the design of future therapeutic strategies to treat patients with brain metastasis.