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

• Type of Material: Article
• Authors: Lisa Sudmeier, Emory University; Kimberly Hoang, Emory University; Edjah Nduom, Emory University; Andreas Wieland, Emory University; Stewart Neill, Emory University; Matthew Schniederjan, Emory University; Suresh Ramalingam, Emory University; Jeffrey Olson, Emory University; Rafi Ahmed, Emory University; William Hudson, Emory University
• Language: English
• Date: 2022-05-17
• Publisher: ELSEVIER
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Author(s)
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.xcrm.2022.100620
• Title of Journal or Parent Work: CELL REPORTS MEDICINE
• Volume: 3
• Issue: 5
• Start Page: 100620
• End Page: 100620
• Grant/Funding Information: The Yerkes NHP Genomics Core is supported in part by NIH P51OD011132, and sequencing data was acquired on an Illumina NovaSeq6000 funded by NIH S10OD026799; Research reported in this publication was also supported by the Ambrose Monell Foundation, the Oliver S. and Jennie R. Donaldson Charitable Trust, the National Cancer Institute (NCI) of the NIH under award number P50CA217691, and by the Pediatrics/Winship Flow Cytometry Core of Winship Cancer Institute of Emory University, Children’s Healthcare of Atlanta, and NIH/NCI under award number P30CA138292. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or the American Society of Clinical Oncology or Conquer Cancer.; R.A. is supported by R01AI030048 and P01AI056299 from the National Institutes of Health (NIH). W.H.H. is supported by a Cancer Research Institute Irvington Fellowship from the Cancer Research Institute and K99AI153736 from the NIH.; L.J.S. is supported by a Conquer Cancer Young Investigator Award, a Radiological Society of North America Resident Research Award, and the Nell W. and William Simpson Elkin Fellowship from Emory University.
• Keywords: IMMUNITY; Cell Biology; T-CELLS; Research & Experimental Medicine; LYMPHOCYTES; SIGNATURE; EFFECTOR; EXHAUSTION; EXPRESSION; TERTIARY LYMPHOID STRUCTURES; PD-1; Life Sciences & Biomedicine; Medicine, Research & Experimental; Science & Technology; PERIPHERAL-BLOOD
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Pathology; Health Sciences, Oncology

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.