Research

Previously, we showed that brain metastases are well infiltrated by exhausted CD8+ T cells, which are the targets of immune checkpoint blockade cancer therapies. These exhausted CD8+ T cells comprise multiple phenotypically-diverse populations. One of these populations, which appears to be the most exhausted and most likely tumor-specific, preferentially occupies niches within the brain metastasis parenchyma. Conversely, another population, which is enriched for bystander CD8+ T cells, is more prevalent in the brain metastasis inflammatory stroma. Our analysis of the brain metastasis microenvironment further revealed discrete signaling niches based on expression of signaling molecules, suggesting that CD8+ T cell subsets receive markedly different inputs depending on their location within the brain metastasis microenvironment. Interaction between the brain environment and immune cells may drive which CD8+ T cell populations exit the vasculature and infiltrate brain metastases and further influence functional and phenotypic changes of tumor-resident CD8+ T cells.

Our work aims to understand the interplay between the brain and tumor microenvironments and how the unique brain microenvironment affects immune cell phenotype and function. We also study how cancer treatments, including radiation and immunotherapy, alter brain-infiltrating immune cell phenotypes. As anti-tumor inflammatory responses in the brain may have deleterious side effects such as encephalitis, another focus of our work is long-term changes to the brain microenvironment with cancer treatment and ways to mitigate adverse neurologic events. The overarching goal of this work is to develop safe immunotherapeutic strategies with enhanced efficacy in the brain.