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Tumor Interferon Signaling Initiates...

Benci, Joseph L.

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Tumor Interferon Signaling Initiates and Sustains a Multigenic Resistance Program to Immune Checkpoint Blockade.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Tumor Interferon Signaling Initiates and Sustains a Multigenic Resistance Program to Immune Checkpoint Blockade./
Author:	Benci, Joseph L.
Published:	Ann Arbor : ProQuest Dissertations & Theses, : 2017,
Description:	115 p.
Notes:	Source: Dissertations Abstracts International, Volume: 79-04, Section: B.
Contained By:	Dissertations Abstracts International79-04B.
Subject:	Molecular biology. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=10284597
ISBN:	9780355181753

Tumor Interferon Signaling Initiates and Sustains a Multigenic Resistance Program to Immune Checkpoint Blockade.
Benci, Joseph L.

Tumor Interferon Signaling Initiates and Sustains a Multigenic Resistance Program to Immune Checkpoint Blockade. - Ann Arbor : ProQuest Dissertations & Theses, 2017 - 115 p.

Source: Dissertations Abstracts International, Volume: 79-04, Section: B.

Thesis (Ph.D.)--University of Pennsylvania, 2017.

This item is not available from ProQuest Dissertations & Theses.

Therapeutic blockade of the CTLA4 and/or PD1 immune checkpoint pathways has resulted in significant anti-tumor responses in broad variety of cancer types, but resistance is common. Using mouse models of metastatic melanoma and breast cancer in combination with CRISPR/Cas9 to selectively delete genes in our tumor cells, we demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Furthermore, we show that this interferon driven resistance mechanism primarily occurs in ICB resistant tumors and not in ICB responsive tumors. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways, and expands distinct T cell populations with improved anti-tumor functions despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.

ISBN: 9780355181753Subjects--Topical Terms:

517296
Molecular biology.

Tumor Interferon Signaling Initiates and Sustains a Multigenic Resistance Program to Immune Checkpoint Blockade.
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245 1 0 $a Tumor Interferon Signaling Initiates and Sustains a Multigenic Resistance Program to Immune Checkpoint Blockade.
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520 $a Therapeutic blockade of the CTLA4 and/or PD1 immune checkpoint pathways has resulted in significant anti-tumor responses in broad variety of cancer types, but resistance is common. Using mouse models of metastatic melanoma and breast cancer in combination with CRISPR/Cas9 to selectively delete genes in our tumor cells, we demonstrate that prolonged interferon signaling orchestrates PDL1-dependent and PDL1-independent resistance to immune checkpoint blockade (ICB), and to combinations such as radiation plus anti-CTLA4. Furthermore, we show that this interferon driven resistance mechanism primarily occurs in ICB resistant tumors and not in ICB responsive tumors. Persistent type II interferon signaling allows tumors to acquire STAT1-related epigenomic changes and augments expression of interferon-stimulated genes and ligands for multiple T cell inhibitory receptors. Both type I and II interferons maintain this resistance program. Crippling the program genetically or pharmacologically interferes with multiple inhibitory pathways, and expands distinct T cell populations with improved anti-tumor functions despite expressing markers of severe exhaustion. Consequently, tumors resistant to multi-agent ICB are rendered responsive to ICB monotherapy. Finally, we observe that biomarkers for interferon-driven resistance associate with clinical progression after anti-PD1 therapy. Thus, the duration of tumor interferon signaling augments adaptive resistance and inhibition of the interferon response bypasses requirements for combinatorial ICB therapies.
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