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

Format:

Book

Manuscript

Thesis/Dissertation

Author/Creator:

Benci, Joseph L., author.

Contributor:

Minn, Andy J., degree supervisor.

Kambayashi, Taku, degree committee member.

Keith, Brian D., degree committee member.

Vonderheide, Robert H., degree committee member.

Wherry, E. John, degree committee member.

University of Pennsylvania. Department of Cell and Molecular Biology, degree granting institution.

Language:

English

Subjects (All):

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Local Subjects:

Penn dissertations--Cell and molecular biology.

Cell and molecular biology--Penn dissertations.

Physical Description:

vi, 109 leaves : illustrations ; 29 cm

Production:

[Philadelphia, Pennsylvania] : University of Pennsylvania, 2017.

Summary:

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.

Notes:

Ph. D. University of Pennsylvania 2017.

Department: Cell and Molecular Biology.

Supervisor: Andy J. Minn.

Includes bibliographical references.

OCLC:

1231651942