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Regulating Antigen Presentation and ...

Oh, Claire Yan-Cheer.

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Regulating Antigen Presentation and Unmasking New Cancer Antigens through ALK, RET, and MEK Inhibitors.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Regulating Antigen Presentation and Unmasking New Cancer Antigens through ALK, RET, and MEK Inhibitors./
Author:	Oh, Claire Yan-Cheer.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2019,
Description:	109 p.
Notes:	Source: Dissertations Abstracts International, Volume: 80-11, Section: B.
Contained By:	Dissertations Abstracts International80-11B.
Subject:	Therapy. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=13877922
ISBN:	9781392137772

Regulating Antigen Presentation and Unmasking New Cancer Antigens through ALK, RET, and MEK Inhibitors.
Oh, Claire Yan-Cheer.

Regulating Antigen Presentation and Unmasking New Cancer Antigens through ALK, RET, and MEK Inhibitors. - Ann Arbor : ProQuest Dissertations & Theses, 2019 - 109 p.

Source: Dissertations Abstracts International, Volume: 80-11, Section: B.

Thesis (Ph.D.)--Weill Medical College of Cornell University, 2019.

This item must not be added to any third party search indexes.

The low frequency of tumor-associated antigens and the downregulation of HLA in some cancers present a challenge to T cell based cancer therapies. The interaction between the TCR of the T cell and peptide/ HLA complexes on the cancer cell is critical for T cell recognition and effective killing of tumor cells in immune surveillance and in immunotherapies. We showed inhibition of the MAPK pathway with MEK inhibitors led to increased HLA surface, protein, and transcript levels. Moreover, we showed there was an inverse relationship seen with pERK levels and surface HLA levels. Treatment with small molecule inhibitors against ALK and RET, two receptor tyrosine kinases that feed into the MAPK pathway and are mutated in certain cancers, produced a dose-related increase in surface HLA, as well as corresponding increases in transcript and protein levels of HLA and antigen processing machinery in cells bearing these mutated kinases. Increases in HLA surface expression up to 3- to 4-fold were seen in vitro after drug treatment. Upregulation of antigen presentation and HLA cell surface expression were seen in vivo after RET and ALK inhibitor treatment. Interestingly, PD-L1 levels also were decreased with ALK inhibitor treatment. Mass spectrometry of the eluted peptides presented by the HLA class I of cancer cells showed that ALK and RET inhibition also led to large changes in the immunopeptidome, with the appearance of hundreds of new antigens, including T cell epitopes associated with impaired peptide processing (TEIPP) and peptides that elicited human T cell responses. Killing assays in vitro showed 20% increased tumor lysis after RET inhibition. Hence, RET and ALK based oncogenesis may provide a new mechanism of escape of immune surveillance by downregulating antigen presentation during the oncogenic process. Therefore, pharmacological inhibitors of RET and ALK could be a useful adjuvant for T cell based therapies by increasing presentation and enhancement of new, immunogenic, cancer associated antigens.

ISBN: 9781392137772Subjects--Topical Terms:

3343697
Therapy.

Regulating Antigen Presentation and Unmasking New Cancer Antigens through ALK, RET, and MEK Inhibitors.
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245 1 0 $a Regulating Antigen Presentation and Unmasking New Cancer Antigens through ALK, RET, and MEK Inhibitors.
260 1 $a Ann Arbor : $b ProQuest Dissertations & Theses, $c 2019
300 $a 109 p.
500 $a Source: Dissertations Abstracts International, Volume: 80-11, Section: B.
500 $a Publisher info.: Dissertation/Thesis.
500 $a Advisor: Scheinberg, David A.
502 $a Thesis (Ph.D.)--Weill Medical College of Cornell University, 2019.
506 $a This item must not be added to any third party search indexes.
506 $a This item must not be sold to any third party vendors.
520 $a The low frequency of tumor-associated antigens and the downregulation of HLA in some cancers present a challenge to T cell based cancer therapies. The interaction between the TCR of the T cell and peptide/ HLA complexes on the cancer cell is critical for T cell recognition and effective killing of tumor cells in immune surveillance and in immunotherapies. We showed inhibition of the MAPK pathway with MEK inhibitors led to increased HLA surface, protein, and transcript levels. Moreover, we showed there was an inverse relationship seen with pERK levels and surface HLA levels. Treatment with small molecule inhibitors against ALK and RET, two receptor tyrosine kinases that feed into the MAPK pathway and are mutated in certain cancers, produced a dose-related increase in surface HLA, as well as corresponding increases in transcript and protein levels of HLA and antigen processing machinery in cells bearing these mutated kinases. Increases in HLA surface expression up to 3- to 4-fold were seen in vitro after drug treatment. Upregulation of antigen presentation and HLA cell surface expression were seen in vivo after RET and ALK inhibitor treatment. Interestingly, PD-L1 levels also were decreased with ALK inhibitor treatment. Mass spectrometry of the eluted peptides presented by the HLA class I of cancer cells showed that ALK and RET inhibition also led to large changes in the immunopeptidome, with the appearance of hundreds of new antigens, including T cell epitopes associated with impaired peptide processing (TEIPP) and peptides that elicited human T cell responses. Killing assays in vitro showed 20% increased tumor lysis after RET inhibition. Hence, RET and ALK based oncogenesis may provide a new mechanism of escape of immune surveillance by downregulating antigen presentation during the oncogenic process. Therefore, pharmacological inhibitors of RET and ALK could be a useful adjuvant for T cell based therapies by increasing presentation and enhancement of new, immunogenic, cancer associated antigens.
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