1 option
Persistent Cancer Cells Alter Interferon Signaling After Immune Checkpoint Blockade / Darwin Ye.
- Format:
- Book
- Thesis/Dissertation
- Author/Creator:
- Ye, Darwin, author.
- Language:
- English
- Subjects (All):
- Cellular biology.
- Oncology.
- Mental health.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Local Subjects:
- Cellular biology.
- Oncology.
- Mental health.
- Cell and Molecular Biology--Penn dissertations.
- Penn dissertations--Cell and Molecular Biology.
- Physical Description:
- 1 online resource (118 pages)
- Distribution:
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- Contained In:
- Dissertations Abstracts International 85-08B.
- Place of Publication:
- [Philadelphia, Pennsylvania] : University of Pennsylvania, 2022.
- Language Note:
- English
- Summary:
- Immune checkpoint blockade (ICB) therapies represent a groundbreaking paradigm in cancer treatment, reshaping clinical approaches. Despite their efficacy, relapse remains a common challenge with poorly understood acquired resistance mechanisms. In this study, leveraging multiple mouse models of ICB relapse, we identify that the features of acquired resistance in cancer cells include: 1) heightened expression of resistance-associated interferon-stimulated genes (ISGs), 2) persistent virus mimicry linked to endogenous retroelement depression, dsRNA accumulation, and heightened pattern recognition receptor (PRR) signaling, and 3) consequential epigenetic modifications in resistant tumor subclones.We demonstrate that subjecting cancer cells to chronic interferon (IFN) stimulation over 3-4 weeks instigates features associated with IFN-driven resistance, contingent upon the dsRNA PRR MDA5. Intriguingly, inhibition of IFN signaling through a JAKi/TBK1i combination for a comparable duration induces a reversal of these IFN resistance-associated characteristics. Our study identifies a mechanism wherein prolonged IFN exposure induces epigenetic alterations and sustained virus mimicry which in turn are required for the upregulation of resistance-associated ISGs, thus perpetuating acquired resistance to ICB. This work enhances our understanding of the evolution between the immune system and cancer cells during ICB therapies with implications for refining future ICB therapy combinations.
- Notes:
- Source: Dissertations Abstracts International, Volume: 85-08, Section: B.
- Advisors: Minn, Andy J.; Committee members: Weitzman, Matthew; Henao-Mejia, Jorge; Beatty, Gregory.
- Department: Cell and Molecular Biology.
- Ph.D. University of Pennsylvania 2023.
- Local Notes:
- School code: 0175
- ISBN:
- 9798381472004
- Access Restriction:
- Restricted for use by site license.
The Penn Libraries is committed to describing library materials using current, accurate, and responsible language. If you discover outdated or inaccurate language, please fill out this feedback form to report it and suggest alternative language.