Characterization of brain metastasis-specific CD8+ T cells

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PROJECT SUMMARY / ABSTRACT CD8+ T cells are cytotoxic T lymphocytes that directly kill tumor and virally-infected cells. T cell exhaustion, in which CD8+ T cells have impaired cell-killing capacity, occurs with prolonged exposure to viral and cancer antigens and prevents optimal disease control. Immune checkpoint blockade (ICB) targeting CTLA-4 or the PD-1 pathway reinvigorates exhausted CD8+ T cells to promote tumor cell killing. Multiple trials have demonstrated the efficacy of ICB in shrinking or eliminating tumors and prolonging survival; however, intracranial tumors are more refractory to ICB therapy than extracranial tumors. Brain metastases affect a significant number of cancer patients and are associated with poor overall survival. Therefore, novel strategies are urgently needed to improve the treatment of tumors that have metastasized to the brain. Development of novel immunotherapeutic agents relies on a detailed characterization of CD8+ T cell heterogeneity in brain metastases. My preliminary data show that there are three distinct populations of CD8+ T cells in human brain metastases, one of which is defined by a terminally differentiated transcriptional phenotype. Using a murine chronic infection model, I have also demonstrated that brain-infiltrating antigen- specific CD8+ T cells have a unique, tissue-specific transcriptional phenotype, which is conserved in a subset of the CD8+ T cells infiltrating human brain metastases. Because of this differential gene expression pattern, I hypothesize that there may be novel co-inhibitory molecules expressed by brain-infiltrating antigen-specific CD8+ T cells. Blocking these molecules may improve therapeutic efficacy of PD-1 pathway blockade and enhance the effector function of exhausted CD8+ T cells in the brain. This project has three goals. First, I will comprehensively characterize the phenotype of CD8+ T cells infiltrating human brain metastases and determine how clonotypes that are shared with circulating CD8+ T cells respond to treatment with immunotherapies. Second, I will identify genes that are differentially expressed by brain-infiltrating CD8+ T cells after ICB and test the function of these genes using the murine LCMV model of CD8+ T cell exhaustion. Finally this grant will support my transition to independence from a trainee in Dr. Rafi Ahmed’s lab, to leading an independent research group.