Author ORCID Identifier
https://orcid.org/0000-0001-5062-4514
Date of Award
Spring 5-12-2026
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Pamela Rosato
Abstract
Glioblastoma (GBM) is the most aggressive primary brain tumor and remains largely resistant to immunotherapies that have transformed the treatment of other malignancies such as melanoma, underscoring the need to better understand the immunosurveillance of brain tumors. CD8+ tumor-infiltrating T cells expressing tissue-residency markers, including CD69 and CD103, have been associated with improved survival across multiple tumor types, including GBM. However, not all tumor-infiltrating CD8+ T cells are specific for tumor antigens. Resident-like T cells specific for common viral infections, including Epstein-Barr virus, influenza A virus, and cytomegalovirus have been found to populate human tumors, including GBM. These bystander (non-tumor specific) memory T cells represent a newly appreciated component of tumor immune microenvironment and their biology remains poorly understood despite their potential to contribute to anti-tumor immunity.
In Chapter II, we use a reductionist approach to dissect the contributions of distinct memory T cell compartments to the resident memory T cell (TRM)-like pool in GBM. We demonstrate that circulating memory T cells (TCircM) can infiltrate brain tumors and rapidly adopt a tissue-residency program. Further, we show that TRM already residing in healthy brain tissue give rise to a substantial proportion of the tumor-infiltrating lymphocytes, and are the primary source of a distinct CD103+ population in brain tumors. Using single-cell RNA sequencing, we further show that pre-existing brain TRM give rise to a transcriptionally distinct TRM-like population in brain tumors that is uniquely poised for cytotoxicity.
Bystander memory T cells have been reported to exert both protective and pathological effects during infections, but their impact on GBM progression has not been well explored. In Chapter III, we assess the functions of both resting and reactivated virus-specific T cells in tumors. We found that in their resting state, tumor-infiltrating virus-specific T cells do not meaningly alter tumor progression. Additionally, while these cells could be reactivated by intratumoral cognate viral peptide, the magnitude of reactivation and ensuing recruitment of other immune cell was markedly attenuated in the tumor compared to the contralateral, non-tumor brain.
Overall, this thesis expands our understanding of brain tumor immunosurveillance and provides valuable insights for the development of novel T cell-based immunotherapies.
Recommended Citation
Kleist, Sierra A., "Investigating the source and function of bystander T cells in glioblastoma" (2026). Dartmouth College Ph.D Dissertations. 508.
https://digitalcommons.dartmouth.edu/dissertations/508
