Distinct phenotypic states and spatial distribution of CD8⁺ T cell clonotypes in human brain metastases.

ABSTRACT: Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8⁺ T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8⁺ T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8⁺ T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8⁺ T cells, including bystander CD8⁺ T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8⁺ T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8⁺ T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.

SUBMITTER: Sudmeier LJ 

PROVIDER: S-EPMC9133402 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature