Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form
D-Scholarship @ Pitt Banner and Links to Homepage

Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells

Shan, Feng (2024) Integrated BATF transcriptional network regulates suppressive intratumoral regulatory T cells. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF
Restricted to University of Pittsburgh users only until 16 September 2026.
Download (11MB) | Request a Copy

Abstract

Human regulatory T cells (Tregs) are crucial regulators of tissue repair, autoimmune diseases, and cancer. However, it is challenging to effectively target Tregs without impacting immune homeostasis, highlighting the importance of targeting tumor-restricted pathways. The transcriptional programs that control intratumoral Treg gene expression selectively remain largely unknown. We profiled single-cell transcriptomes of CD4+ T cells in tumors and peripheral blood from patients with head and neck squamous cell carcinomas (HNSCC), in non-tumor tonsil tissues and in peripheral blood from healthy donors. We identified a subpopulation of activated Tregs expressing multiple tumor necrosis factor receptor (TNFR) genes (TNFR+ Tregs) that is highly enriched in the tumor microenvironment (TME) compared with non-tumor tissue and the periphery. TNFR+ Tregs are associated with worse prognosis in HNSCC and across multiple solid tumor types. Mechanistically, the transcription factor BATF is a central component of a gene regulatory network that governs key aspects of TNFR+ Tregs. CRISPR/Cas9-mediated BATF knockout in human activated Tregs in conjunction with bulk RNA sequencing, immunophenotyping and in vitro functional assays corroborated the central role of BATF as a nexus to limit excessive activation and promote the survival of human activated Tregs. Finally, we identified a suite of surface molecules reflective of the BATF-driven transcriptional network on intratumoral Tregs in patients with HNSCC. These findings uncover a primary transcriptional regulator of highly suppressive intratumoral Tregs, highlighting new potential opportunities for therapeutic intervention in cancer without impacting immune homeostasis.

Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shan, Fengshf43@pitt.edushf430000-0003-3660-8475
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBenos, Takispbenos@ufl.edu
Committee MemberLakkis, Fadilakkisf@upmc.edu
Committee MemberAtianand, Maninjayatianand@pitt.edu
Committee MemberSingh, Harinderharinder@pitt.edu
Thesis AdvisorVignali, Dariodvignali@pitt.edu
Date: 16 September 2024
Date Type: Publication
Defense Date: 12 October 2023
Approval Date: 16 September 2024
Submission Date: 27 October 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 135
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Medicine
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Regulatory T cells, tumor microenvironment, BATF, transcriptional network
Date Deposited: 16 Sep 2024 17:54
Last Modified: 16 Sep 2024 17:54
URI: http://d-scholarship.pitt.edu/id/eprint/45474

Metrics

Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item