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Novel Immunologic Insights and Immunotherapeutic Strategies in Triple Negative Breast Cancer
Novel Immunologic Insights and Immunotherapeutic Strategies in Triple Negative Breast Cancer
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260209102900
- ISBN
- 9798291590232
- DDC
- 610
- 서명/저자
- Novel Immunologic Insights and Immunotherapeutic Strategies in Triple Negative Breast Cancer
- 발행사항
- [Sl] : Case Western Reserve University, 2023
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2023
- 형태사항
- 146 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 주기사항
- Advisor: Moravec, Christine.
- 학위논문주기
- Thesis (Ph.D.)--Case Western Reserve University, 2023.
- 초록/해제
- 요약Given the absence of hormone receptor and HER2 targets, treatment options outside of surgery, if applicable, and chemotherapy are limited in triple-negative breast cancer (TNBC). Associated with aggressive biology and high risk of recurrence and metastasis, TNBC remains the deadliest subtype of breast cancer. TNBCs are more likely to be immune infiltrated than other BC subtypes, which has led to increased investigation into immunotherapeutic strategies, particularly immune checkpoint inhibitors (ICIs). However, the vast majority of patients do not respond to ICIs, and those who do respond are unlikely to experience durable responses. Therefore, it is essential to elucidate mechanisms of treatment response and resistance in order to improve immunotherapeutic outcomes in TNBC. Here, we investigate differences in the transcriptomic landscapes of pre-treatment tumor samples from ICI treatment responders and non-responders using bulk RNA-sequencing as well as describe characteristic differences between the PBMCs in treatment responders and non-responders using single-cell RNA-sequencing, single-cell proteomics, and flow cytometry. Finally, we investigate a strategy to improve T cell infiltration in TNBC tumors via T cell engineering using 慣-lactalbumin as an antigenic target. From pre-treatment tumor biopsies from patients who underwent treatment with ICI, we identified that those who experienced durable response were those with a baseline concurrent infiltration of B cells and follicular helper T cells, a phenomena characterized by enriched IGHG1 expression on bulk-RNA sequencing, which was associated with improved overall survival. From patient PBMCs, we learned that in dual therapy with blockade of the PD-1/PD-L1 axis and chemotherapy, treatment response may be driven by CD33+ myeloid cell phenotypes, with IL-1b playing a critical facilitating role. Finally, we reinforced that 慣-lactalbumin, a protein conditionally expressed during late pregnancy and lactation, is also expressed in TNBC tumors and cell lines. T cells reactive to 慣-lactalbumin can particularly be found in the T cell repertoires of healthy parous women and their associated T cell receptors can be harnessed to redirect human T cells against antigenic targets in TNBC. Taken together, these insights may be used to predict and improve lymphocytic infiltration of TNBC tumors, improve responses to ICI, and transform immunotherapeutic management of TNBC.
- 일반주제명
- Medicine
- 일반주제명
- Oncology
- 일반주제명
- Immunology
- 일반주제명
- Cellular biology
- 키워드
- Immunotherapy
- 키워드
- T cell therapy
- 기타저자
- Case Western Reserve University Molecular Medicine
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■1001 ▼aWilkerson, Avia D.
■24510▼aNovel Immunologic Insights and Immunotherapeutic Strategies in Triple Negative Breast Cancer
■260 ▼a[Sl]▼bCase Western Reserve University▼c2023
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2023
■300 ▼a146 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Moravec, Christine.
■5021 ▼aThesis (Ph.D.)--Case Western Reserve University, 2023.
■520 ▼aGiven the absence of hormone receptor and HER2 targets, treatment options outside of surgery, if applicable, and chemotherapy are limited in triple-negative breast cancer (TNBC). Associated with aggressive biology and high risk of recurrence and metastasis, TNBC remains the deadliest subtype of breast cancer. TNBCs are more likely to be immune infiltrated than other BC subtypes, which has led to increased investigation into immunotherapeutic strategies, particularly immune checkpoint inhibitors (ICIs). However, the vast majority of patients do not respond to ICIs, and those who do respond are unlikely to experience durable responses. Therefore, it is essential to elucidate mechanisms of treatment response and resistance in order to improve immunotherapeutic outcomes in TNBC. Here, we investigate differences in the transcriptomic landscapes of pre-treatment tumor samples from ICI treatment responders and non-responders using bulk RNA-sequencing as well as describe characteristic differences between the PBMCs in treatment responders and non-responders using single-cell RNA-sequencing, single-cell proteomics, and flow cytometry. Finally, we investigate a strategy to improve T cell infiltration in TNBC tumors via T cell engineering using 慣-lactalbumin as an antigenic target. From pre-treatment tumor biopsies from patients who underwent treatment with ICI, we identified that those who experienced durable response were those with a baseline concurrent infiltration of B cells and follicular helper T cells, a phenomena characterized by enriched IGHG1 expression on bulk-RNA sequencing, which was associated with improved overall survival. From patient PBMCs, we learned that in dual therapy with blockade of the PD-1/PD-L1 axis and chemotherapy, treatment response may be driven by CD33+ myeloid cell phenotypes, with IL-1b playing a critical facilitating role. Finally, we reinforced that 慣-lactalbumin, a protein conditionally expressed during late pregnancy and lactation, is also expressed in TNBC tumors and cell lines. T cells reactive to 慣-lactalbumin can particularly be found in the T cell repertoires of healthy parous women and their associated T cell receptors can be harnessed to redirect human T cells against antigenic targets in TNBC. Taken together, these insights may be used to predict and improve lymphocytic infiltration of TNBC tumors, improve responses to ICI, and transform immunotherapeutic management of TNBC.
■590 ▼aSchool code: 0042.
■650 4▼aMedicine
■650 4▼aOncology
■650 4▼aImmunology
■650 4▼aCellular biology
■653 ▼aTriple negative breast cancer
■653 ▼aImmunotherapy
■653 ▼aImmune checkpoint inhibitors
■653 ▼aT cell therapy
■653 ▼aPre-treatment tumor biopsies
■690 ▼a0564
■690 ▼a0992
■690 ▼a0982
■690 ▼a0379
■71020▼aCase Western Reserve University▼bMolecular Medicine.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0042
■791 ▼aPh.D.
■792 ▼a2023
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17365944▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
