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TOX2 and Tox at the Intersection of Central Memory and Exhaustion in Human Car T Cells- [electronic resource]
TOX2 and Tox at the Intersection of Central Memory and Exhaustion in Human Car T Cells- [electronic resource]
상세정보
- 자료유형
- 학위논문파일 국외
- 최종처리일시
- 20240214101816
- ISBN
- 9798380388689
- DDC
- 574
- 저자명
- Collins, Sierra.
- 서명/저자
- TOX2 and Tox at the Intersection of Central Memory and Exhaustion in Human Car T Cells - [electronic resource]
- 발행사항
- [S.l.]: : University of Pennsylvania., 2023
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- 형태사항
- 1 online resource(148 p.)
- 주기사항
- Source: Dissertations Abstracts International, Volume: 85-03, Section: B.
- 주기사항
- Advisor: Berger, Shelley L.
- 학위논문주기
- Thesis (Ph.D.)--University of Pennsylvania, 2023.
- 사용제한주기
- This item must not be sold to any third party vendors.
- 초록/해제
- 요약CAR T therapy has provided a breakthrough in the treatment of hematologic malignancies, showing remarkable efficacy in cancers such as leukemia and lymphoma. However, the success of CAR T therapy in treating solid tumors has been limited due to T cell exhaustion, which limits their proliferation and cytotoxicity when chronically stimulated with antigen, such as in cancer. Genetic modification of CAR T cells is one approach to improve tumor killing capacity. We profiled a patient with chronic lymphocytic leukemia (CLL) who responded exceedingly well to CAR T therapy, finding increased transcription and chromatin opening at the transcription factor TOX2. We show, in an in vitro CAR T model, that TOX2 is required for the development of central memory T cells (TCMs), the preponderance of which underlay the positive therapeutic response. Our results show that TOX2 can induce a TCM phenotype and gene expression program by binding to the promoters of many TCM genes. In contrast, some studies in mice position TOX2 as a positive regulator of T cell exhaustion, like the closely related transcription factor TOX. We characterize TOX as a master regulator of T cell exhaustion in mice. We show that TOX works with a chromatin regulator to bind chromatin and positively regulate transcription of other exhaustion-related genes in mice, such as TOX2. Despite this similarity in mouse models of exhaustion, while TOX2 promotes TCM in our model of human CAR T therapy, we find that TOX is not required for TCMs, since TCMs increase when TOX expression is lost. However, when TOX2 is overexpressed at very high levels, it begins to induce exhaustion gene signatures and bind to exhaustion-related loci. We propose a model for TOX2 as a regulator of both central memory and exhaustion-two T cell subsets that are surprisingly similar-and we posit that the exact level of TOX2 expression could be responsible for the balance between them in certain contexts. Our results present a new role for TOX2 as a regulator of central memory, which distinguishes it from TOX, and introduce the potential for TOX2 overexpression to improve the potency of CAR T therapy.
- 일반주제명
- Biology.
- 일반주제명
- Immunology.
- 일반주제명
- Genetics.
- 키워드
- CAR T therapy
- 키워드
- Immunotherapy
- 키워드
- TOX2 expression
- 키워드
- Gene expression
- 기타저자
- University of Pennsylvania Cell and Molecular Biology
- 기본자료저록
- Dissertations Abstracts International. 85-03B.
- 기본자료저록
- Dissertation Abstract International
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■00520240214101816
■006m o d
■007cr#unu||||||||
■020 ▼a9798380388689
■035 ▼a(MiAaPQ)AAI30571143
■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aCollins, Sierra.
■24510▼aTOX2 and Tox at the Intersection of Central Memory and Exhaustion in Human Car T Cells▼h[electronic resource]
■260 ▼a[S.l.]:▼bUniversity of Pennsylvania. ▼c2023
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2023
■300 ▼a1 online resource(148 p.)
■500 ▼aSource: Dissertations Abstracts International, Volume: 85-03, Section: B.
■500 ▼aAdvisor: Berger, Shelley L.
■5021 ▼aThesis (Ph.D.)--University of Pennsylvania, 2023.
■506 ▼aThis item must not be sold to any third party vendors.
■520 ▼aCAR T therapy has provided a breakthrough in the treatment of hematologic malignancies, showing remarkable efficacy in cancers such as leukemia and lymphoma. However, the success of CAR T therapy in treating solid tumors has been limited due to T cell exhaustion, which limits their proliferation and cytotoxicity when chronically stimulated with antigen, such as in cancer. Genetic modification of CAR T cells is one approach to improve tumor killing capacity. We profiled a patient with chronic lymphocytic leukemia (CLL) who responded exceedingly well to CAR T therapy, finding increased transcription and chromatin opening at the transcription factor TOX2. We show, in an in vitro CAR T model, that TOX2 is required for the development of central memory T cells (TCMs), the preponderance of which underlay the positive therapeutic response. Our results show that TOX2 can induce a TCM phenotype and gene expression program by binding to the promoters of many TCM genes. In contrast, some studies in mice position TOX2 as a positive regulator of T cell exhaustion, like the closely related transcription factor TOX. We characterize TOX as a master regulator of T cell exhaustion in mice. We show that TOX works with a chromatin regulator to bind chromatin and positively regulate transcription of other exhaustion-related genes in mice, such as TOX2. Despite this similarity in mouse models of exhaustion, while TOX2 promotes TCM in our model of human CAR T therapy, we find that TOX is not required for TCMs, since TCMs increase when TOX expression is lost. However, when TOX2 is overexpressed at very high levels, it begins to induce exhaustion gene signatures and bind to exhaustion-related loci. We propose a model for TOX2 as a regulator of both central memory and exhaustion-two T cell subsets that are surprisingly similar-and we posit that the exact level of TOX2 expression could be responsible for the balance between them in certain contexts. Our results present a new role for TOX2 as a regulator of central memory, which distinguishes it from TOX, and introduce the potential for TOX2 overexpression to improve the potency of CAR T therapy.
■590 ▼aSchool code: 0175.
■650 4▼aBiology.
■650 4▼aImmunology.
■650 4▼aGenetics.
■653 ▼aCAR T therapy
■653 ▼aImmunotherapy
■653 ▼aT cell exhaustion
■653 ▼aTOX2 expression
■653 ▼aGene expression
■690 ▼a0306
■690 ▼a0982
■690 ▼a0369
■71020▼aUniversity of Pennsylvania▼bCell and Molecular Biology.
■7730 ▼tDissertations Abstracts International▼g85-03B.
■773 ▼tDissertation Abstract International
■790 ▼a0175
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T16934886▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
■980 ▼a202402▼f2024
