Biology subjects

Kleist, S. A.

Publications and source records attributed to Kleist, S. A..

4 recordsLinked to original sources

bioRxiv2026

Circulating and brain-resident memory CD8+ T cells seed distinct bystander TRM-like populations in glioblastoma

Across cancers, tumor-infiltrating CD8+ T cells expressing the tissue-resident memory T cell (TRM) markers CD69 and CD103 are strongly associated with favorable clinical outcomes. However, a substantial fraction of these cells in human tumors are not tumor-specific, but instead recognize unrelated viral antigens. These virus-specific bystander TRM-like cells are prevalent in tumors and retain functional potential, raising interest in strategies that leverage pre-existing antiviral immunity for cancer immunotherapy. Yet their origins and differentiation states remain poorly defined, limiting both the interpretation of residency-based tumor-infiltrating lymphocyte (TIL) phenotyping and efforts to rationally harness these TRM-like cells. Here, using mouse models of GBM and melanoma, we demonstrate that resting circulating memory T cells trafficked into tumors via GPCR-dependent signaling and rapidly adopted a tissue-resident phenotype, independent of cognate antigen. Strikingly, in GBM, but not melanoma, pre-existing brain TRM contributed substantially to the bystander TIL compartment and were the dominant source of CD69+/CD103+ bystander T cells, revealing a tumor- and tissue-specific origin for this subset. These findings were further supported by transcriptional analysis of T cell receptor clones present in both paired patient GBM tumor and peritumoral brain, which identified shared features with TRM-derived TILs in mouse GBM. Overall, this work provides new insight into tumor immunosurveillance, inform the interpretation of CD69+/CD103- and CD103+ TIL populations, and lay a foundation for immunotherapeutic strategies aimed at harnessing circulating and pre-existing virus-specific TRM populations in tumors.

immunology↗

bioRxiv2025

Endocrine therapy induces oxidative stress in ER+ breast cancer that sensitizes persister cells to ferroptosis

Despite endocrine therapy, recurrence and progression of estrogen receptor alpha (ER)-positive breast cancer remain significant clinical problems. We therefore sought to identify mechanisms underlying endocrine-tolerant persistence. Endocrine-tolerant persister ER+ breast cancer cells were oxidatively stressed during endocrine therapy. Proteomic analysis revealed upregulation of antioxidant-driving enzymes including glutathione peroxidase 4 (GPX4) in persisters. Relief of oxidative stress enhanced persister fitness. The increased oxidative state of persisters enabled lipid peroxidation and ferroptosis. Persisters had an altered lipidome with increased levels of polyunsaturated fatty acids prone to peroxidation, which was attributable in part to increased lysophosphatidylcholine acyltyransferase 3 (LPCAT3, MBOAT5) expression via loss of ER-mediated repression during endocrine therapy. Treatment with the GPX4 inhibitor RSL3 enhanced the anti-persister effects of endocrine-based therapies in xenograft-bearing mice. These findings supporting the development of therapeutic strategies to leverage the oxidative stress induced by endocrine-based therapies and drive ferroptosis as a treatment for ER+ breast cancer. Statement of SignificanceEndocrine therapy increases oxidative stress and sensitizes endocrine-tolerant persister ER+ breast cancer cells to ferroptosis, indicating that therapies targeting this metabolic dependency could help prevent disease recurrence and progression.

cancer biology↗

bioRxiv2024

Alarm functions of PD-1+ brain resident memory T cells

Resident memory T cells (TRM) have been described in barrier tissues as having a sensing and alarm function where, upon sensing cognate antigen, they alarm the surrounding tissue and orchestrate local recruitment and activation of immune cells. In the immunologically unique and tightly restricted CNS, it remains unclear if and how brain TRM, which express the inhibitory receptor PD-1, alarm the surrounding tissue during antigen re-encounter. Here, we reveal that TRM are sufficient to drive the rapid remodeling of the brain immune landscape through activation of microglia, DCs, NK cells, and B cells, expansion of Tregs, and recruitment of macrophages and monocytic dendritic cells. Moreover, we report that while PD-1 restrains granzyme B expression by reactivated brain TRM, it has no effect on cytotoxicity or downstream alarm responses. We conclude that TRM are sufficient to trigger rapid immune activation and recruitment in the CNS and may have an unappreciated role in driving neuroinflammation.

immunology↗

bioRxiv2024

CD39 is expressed on functional effector and tissue resident memory CD8+ T cells

The ecto-ATPase CD39 is expressed on exhausted CD8+ T cells in chronic viral infection and has been proposed as a marker of tumor-specific CD8+ T cells in cancer, but the role of CD39 in an effector and memory T cell response has not been clearly defined. We report that CD39 is expressed on antigen-specific CD8+ short-lived effector cells (SLECs), while its co-ecto-enzyme, CD73, is found on memory precursor effector cells (MPEC) in vivo. Inhibition of CD39 enzymatic activity during in vitro T cell priming enhances MPEC differentiation in vivo after transfer and infection. The enriched MPEC phenotype is associated with enhanced tissue resident memory (TRM) establishment in the brain and salivary gland following an acute intranasal viral infection, suggesting that CD39 ATPase activity plays a role in memory CD8+ T cell differentiation. We also show that CD39 is expressed on human and murine TRM across several non-lymphoid tissues and melanoma, while CD73 is expressed on both circulating and resident memory subsets in mice. In contrast to exhausted CD39+ T cells in chronic infection, CD39+ TRM are fully functional when stimulated ex vivo with cognate antigen. This work further expands the identity of CD39 beyond a T cell exhaustion marker.

immunology↗