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[ subject:"Oncology." ]
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Immune Checkpoints PD-1/PD-L1 and Na...
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Siu, Hon Lam Elaine.
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Immune Checkpoints PD-1/PD-L1 and Natural Killer Cells in Chemo-resistant Colorectal Cancer.
紀錄類型:
書目-電子資源 : Monograph/item
正題名/作者:
Immune Checkpoints PD-1/PD-L1 and Natural Killer Cells in Chemo-resistant Colorectal Cancer./
作者:
Siu, Hon Lam Elaine.
出版者:
Ann Arbor : ProQuest Dissertations & Theses, : 2019,
面頁冊數:
285 p.
附註:
Source: Dissertations Abstracts International, Volume: 81-09, Section: B.
Contained By:
Dissertations Abstracts International81-09B.
標題:
Oncology. -
電子資源:
http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=27784076
ISBN:
9781392643204
Immune Checkpoints PD-1/PD-L1 and Natural Killer Cells in Chemo-resistant Colorectal Cancer.
Siu, Hon Lam Elaine.
Immune Checkpoints PD-1/PD-L1 and Natural Killer Cells in Chemo-resistant Colorectal Cancer.
- Ann Arbor : ProQuest Dissertations & Theses, 2019 - 285 p.
Source: Dissertations Abstracts International, Volume: 81-09, Section: B.
Thesis (Ph.D.)--The Chinese University of Hong Kong (Hong Kong), 2019.
Colorectal cancer (CRC) is frequently lethal with diverse clinical outcomes and drug responses. Heterogeneity of the tumor microenvironment, including the interaction between tumor cells and immune checkpoints are now becoming increasingly important to tumorigenesis and clinical outcome of patients after the discovery of immunoescape. This study intended to investigate the potential role of PD-1/PD-L1 immune checkpoints in tumor cells and NK cells, in contrast to classical studies demonstrating the interactions of PD-L1 and PD-1 between tumor cells and T cells respectively.Expression of PD-L1 in tumor cells/immune infiltrates in the tumor microenvironment was examined by immunohistochemistry and PD-L1 upregulation was found to be associated with poor response in CRC patients with XELOX/FOLFOX chemotherapy (p=0.006). Further investigation on the immune profiles of the tumor microenvironment by multiplex immunofluorescence with spatial computational analysis revealed an intense infiltration of regulatory T cells and alternatively activated macrophages in the tumor bulk of the poor responders, demonstrating the potential of immune signatures to serve as surrogate marker of treatment response for chemotherapy.Two CRC cell lines, HT29 and HCT116 which represented the mismatch repair-proficient and -deficient status respectively, were exposed to fluorouracil/oxaliplatin and selected for the chemo-resistant populations. The chemo-resistant cells demonstrated 10-200 fold increased in resistance to respective chemotherapeutic agents, expressed significantly higher PD-L1 at mRNA and protein levels compared to their respective parental cell lines. This corroborated the clinical observation that poor responders of XELOX/FOLFOX chemotherapy associated with elevated PD-L1 expressions in CRCs. Continuation study on the panel of chemo-resistant cells demonstrated that these PD-L1 overexpressed cells comprised cancer stem cell-enriched phenotypes, including the ability to form spheres and colonies, and with enhanced expressions of stemness markers Sox 2 and KLF4. Functional study by silencing of the PD-L1 expressions substantiated its role on modulation of tumor cell resistance to conventional chemotherapeutic agents.Natural killer (NK) cells were isolated from peripheral blood of cancer patients or healthy donors, followed with further ex vivo expansion and activation. The expanded NK cells, compared to naive NK cells from patients, showed diminished PD-1 expressions, enhanced production of functional molecules including perforin and IFNɣ. The co-culture models of CRC and NK cells indicated that the expanded NK cells were able to exert augmented cytotoxic response against the tumor cells. PD-1 antibody treatment further boosted the NK-mediated anti-tumor cytotoxicity, and the chemoresistant cells were similarly sensitive to the NK/PD-1 treatment.Overall, our data supported the translation of immunoscore from the field of oncology research to clinical setting in aiding tissue subtyping and prognosis. The correlation of PD-L1 to chemoresistance and stemness was delineated by examining the phenotypes of the chemo-resistance cells. Most importantly, we demonstrated that the impairment of NK cells from patients can be restored by ex vivo manipulation and further, cytotoxic killing by NK cells in the combination with PD-1 antibody resulted in synergistic antitumor response against both the parental and chemo-resistant cell lines, indicating the potential of such a combination approach in limiting chemoresistance and tumor progression of CRCs, without regard to the underlying mismatch repair status and chemo-responsiveness.
ISBN: 9781392643204Subjects--Topical Terms:
751006
Oncology.
Subjects--Index Terms:
Colorectal cancer
Immune Checkpoints PD-1/PD-L1 and Natural Killer Cells in Chemo-resistant Colorectal Cancer.
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Colorectal cancer (CRC) is frequently lethal with diverse clinical outcomes and drug responses. Heterogeneity of the tumor microenvironment, including the interaction between tumor cells and immune checkpoints are now becoming increasingly important to tumorigenesis and clinical outcome of patients after the discovery of immunoescape. This study intended to investigate the potential role of PD-1/PD-L1 immune checkpoints in tumor cells and NK cells, in contrast to classical studies demonstrating the interactions of PD-L1 and PD-1 between tumor cells and T cells respectively.Expression of PD-L1 in tumor cells/immune infiltrates in the tumor microenvironment was examined by immunohistochemistry and PD-L1 upregulation was found to be associated with poor response in CRC patients with XELOX/FOLFOX chemotherapy (p=0.006). Further investigation on the immune profiles of the tumor microenvironment by multiplex immunofluorescence with spatial computational analysis revealed an intense infiltration of regulatory T cells and alternatively activated macrophages in the tumor bulk of the poor responders, demonstrating the potential of immune signatures to serve as surrogate marker of treatment response for chemotherapy.Two CRC cell lines, HT29 and HCT116 which represented the mismatch repair-proficient and -deficient status respectively, were exposed to fluorouracil/oxaliplatin and selected for the chemo-resistant populations. The chemo-resistant cells demonstrated 10-200 fold increased in resistance to respective chemotherapeutic agents, expressed significantly higher PD-L1 at mRNA and protein levels compared to their respective parental cell lines. This corroborated the clinical observation that poor responders of XELOX/FOLFOX chemotherapy associated with elevated PD-L1 expressions in CRCs. Continuation study on the panel of chemo-resistant cells demonstrated that these PD-L1 overexpressed cells comprised cancer stem cell-enriched phenotypes, including the ability to form spheres and colonies, and with enhanced expressions of stemness markers Sox 2 and KLF4. Functional study by silencing of the PD-L1 expressions substantiated its role on modulation of tumor cell resistance to conventional chemotherapeutic agents.Natural killer (NK) cells were isolated from peripheral blood of cancer patients or healthy donors, followed with further ex vivo expansion and activation. The expanded NK cells, compared to naive NK cells from patients, showed diminished PD-1 expressions, enhanced production of functional molecules including perforin and IFNɣ. The co-culture models of CRC and NK cells indicated that the expanded NK cells were able to exert augmented cytotoxic response against the tumor cells. PD-1 antibody treatment further boosted the NK-mediated anti-tumor cytotoxicity, and the chemoresistant cells were similarly sensitive to the NK/PD-1 treatment.Overall, our data supported the translation of immunoscore from the field of oncology research to clinical setting in aiding tissue subtyping and prognosis. The correlation of PD-L1 to chemoresistance and stemness was delineated by examining the phenotypes of the chemo-resistance cells. Most importantly, we demonstrated that the impairment of NK cells from patients can be restored by ex vivo manipulation and further, cytotoxic killing by NK cells in the combination with PD-1 antibody resulted in synergistic antitumor response against both the parental and chemo-resistant cell lines, indicating the potential of such a combination approach in limiting chemoresistance and tumor progression of CRCs, without regard to the underlying mismatch repair status and chemo-responsiveness.
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