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삼중음성유방암 모델에서 PI3Kγδ저해제와 방사선 병용치료를 통한 PD-1억제제의 항종양면역효과 극대화 전략
Full text link학위논문(박사) -- 서울대학교대학원 : 의과대학 협동과정 종양생물학전공, 2022. 8. 김인아.Introduction: The poor response of breast cancer to immune checkpoint blockade may result from low immunogenicity and the immune-suppressive tumor microenvironment. We hypothesized that combined use of phosphoinositide 3-kinase (PI3K) inhibitor to obstruct immune suppression and radiation therapy (RT) as a in situ tumor vaccination would reinforce the antitumor immune effect of PD-1 blockade as an immune checkpoint blockade.
Methods: Murine breast cancer cells (4T1) were grown in both immune-competent and immune-deficient BALB/c mice, and tumors were irradiated by 3 fractions of 24 Gy. A PD-1 blockade and a PI3Kγδ inhibitor were then administered every other day for 2 weeks. Flow cytometry analysis and immunohistochemistry served to monitor subsequent changes in immune cell population. Same experiments were performed in humanized patient-derived breast cancer xenograft (Hu-PDX) model, and its RNA of tumor was sequenced to identify immune-related pathways and to profile infiltrated immune cells. Transcriptomic and clinical data were acquired from The Cancer Genome Atlas (TCGA) pan-cancer cohort, and the deconvolution algorithm was used to profile immune cell repertoire.
Results: The triple combination of RT, PD-1 blockade, and PI3Kγδ inhibitor significantly delayed tumor growth, boosted the abscopal effect, and improved animal survival. RT significantly increased CD8+ cytotoxic T-cell fractions, immune-suppressive Tregs, MDSCs, and M2 tumor associated macrophages (TAMs). However, PI3Kγδ inhibitor significantly lowered proportions of Tregs, MDSCs, and M2 TAMs, achieving dramatic gains in splenic, nodal, and tumor CD8+ T-cell populations after triple combination therapy. In a humanized PDX model, triple combination therapy significantly delayed tumor growth and decreased immune suppressive pathways. In TCGA cohort, high Treg/CD8+ T cell and M2/M1 TAM ratios were associated with poor overall patient survival.
Conclusion: These findings indicate PI3Kγδ are clinically relevant targets in an immunosuppressive TME. And combining RT and PD-1 blockade may overcome the therapeutic resistance of immunologically cold tumors such as breast cancer having immunosuppressive tumor microenvironment.유방암은 면역원성이 부족하고, 면역억제성 종양미세환경을 가지고 있기 때문에 면역관문억제제에 대해 치료 저항성이 있다고 알려져 있다. 따라서 본 연구는 면역 억제를 방해하는 포스포이노시타이드 3-인산화효소 (phosphoinositide 3-kinase, PI3K) 저해제와 in situ 종양백신 효과를 유도하는 방사선치료 병용치료를 통한 PD-1억제제의 항종양면역효과를 극대화하고자 하였다.
면역세포를 온전히 가지고 있는 일반생쥐(BALB/c) 및 면역이 결핍된 생쥐(Nude)에서 유방암 세포주를 각각 성장시키고, 총 24 Gy 용량의 방사선을 3회로 나누어 성장된 종양에 조사하였다. 그리고 PD-1억제제와 PI3Kγδ저해제를 이틀에 한 번씩, 2주 동안 투여하였다. 종양 및 비장, 림프절을 추출하고 유세포분석 및 면역세포화학법을 이용하여 각 조직의 면역세포의 군집을 관찰하였다. 동일한 실험 일정으로 환자유래 인간화마우스 (humanized patient-derived breast cancer xenograft, PDX) 모델에서 수행하였고, 실험 종료 후 종양조직에서 RNA를 추출하여 전사체분석을 통해 면역세포의 profile과 면역관련 pathways를 관찰하였다. 또한 Cancer Genome Atlas (TCGA) pan-cancer 코호트에서 전체사 및 임상적 자료를 수집하였고, deconvolution 알고리즘을 사용하여 면역세포의 repertoire를 확인하였다.
그 결과, PI3Kγδ저해제 및 방사선치료, PD-1억제제를 삼중병용치료한 군에서 종양의 성장이 유의미하게 지연되었다. 또한 방사선의 abscopal 효과가 증진되었고 생존률이 증가하였다. 단독 방사선치료는 CD8+ T세포의 군집을 유의미하게 증가시켰지만, 동시에 조절T세포(regulatory T cells, Tregs)와 골수유래 면역억제세포(myeloid-derived suppressor cells, MDSCs) 및 M2 종양관련대식세포(tumor associated macrophages, TAMs)와 같은 면역억제성 세포의 군집 또한 함께 증가시켰다. PI3Kγδ저해제를 투여하였을 때에는 이러한 면역억제성 세포를 효과적으로 저해할 수 있었고 특히 삼중병용치료를 시행한 결과 종양, 비장 및 림프절에 존재하는 CD8+ T세포 군집이 극적으로 증가하였다. 그리고 환자유래 인간화마우스 모델에서도 삼중병용치료가 종양성장의 지연시키고 면역억제성 pathways를 저해시킴을 확인하였다. 마지막으로 TCGA 코호트에서 Treg/CD8+ T세포 및 M2/M1 TAM의 높은 분율과 환자의 낮은 생존률의 유의미한 연관성이 있음을 밝혔다.
이에 본 연구는 면역억제성 종양미세환경에서 PI3Kγδ저해제가 임상적으로 유의미한 타겟이라는 것과 방사선과 PD-1억제제의 병용은 면역억제성 종양 미세환경을 가진 유방암과 같은 면역적으로 cold한 종양의 치료 저항성을 극복할 수 있다는 가능성을 시사한다.I. Introduction 1
II. Materials and Methods 6
1. Preparation of cell lines 6
2. In vivo studies using syngenic murine tumor model 6
3. Bioluminescence imaging 9
4. Immunohistochemistry and immunofluorescent staining, confocal microscopy 9
5. Flow cytometery analysis 10
6. Measurement of interferon (IFN) beta and gamma level 11
7. Generation of humanized patient-derived xenograft (PDX) model 11
8. Humanized PDX-derived tumor mRNA sequencing and bioinformatic analysis 12
9. TCGA data acquisition, immune cell deconvolution, and survival analysis 13
10. Statistical Analysis 14
III. Results 16
1. Combining RT and PI3Kγδ inhibitor with PD-1 blockade resulted in enhanced antitumor effects 16
2. Abscopal effects 23
3. Expression of key molecules according to treatment 28
4. RT and/or PI3Kγδ inhibitor modulated immune cells in the spleen and dLN 35
5. RT and/or PI3Kγδ inhibitor modulated immune cells in the TME 38
6. Transcriptomic analysis of humanized patient-derived xenograft samples 41
7. . Immune cell proportions of TME in The Cancer Genome Atlas pan-cancer cohort 46
IV. Discussion 53
References 59
Abstract in Korean 65박
Going Beyond Counting First Authors in Author Co-citation Analysis
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counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
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Dispelling the Myths Behind First-author Citation Counts
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use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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