Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

Joseph L Benci; Bihui Xu; Yu Qiu; Tony J Wu; Hannah Dada; Christina Twyman-Saint Victor; Lisa Cucolo; David S M Lee; Kristen E Pauken; Alexander C Huang; Tara C Gangadhar; Ravi K Amaravadi; Lynn M Schuchter; Michael D Feldman; Hemant Ishwaran; Robert H Vonderheide; Amit Maity; E John Wherry; Andy J Minn

doi:10.1016/j.cell.2016.11.022

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Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

Journal article

Open access

Peer reviewed

Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade

Joseph L Benci, Bihui Xu, Yu Qiu, Tony J Wu, Hannah Dada, Christina Twyman-Saint Victor, Lisa Cucolo, David S M Lee, Kristen E Pauken, Alexander C Huang, …

Cell (Cambridge), Vol.167(6), pp.1540-1554.e12

2016-12-01

DOI: https://doi.org/10.1016/j.cell.2016.11.022

PMCID: PMC5385895

PMID: 27912061

Abstract

Neoplasm Transplantation

Humans

Melanoma - radiotherapy

Radioimmunotherapy

Drug Resistance, Neoplasm

Interferons - immunology

B7-H1 Antigen - metabolism

Animals

Heterografts

Melanoma - immunology

Melanoma - drug therapy

Cell Line, Tumor

STAT1 Transcription Factor

T-Lymphocytes - immunology

Mice

CTLA-4 Antigen - antagonists & inhibitors

Melanoma - therapy

Therapeutic blocking of the PD1 pathway results in significant tumor responses, but resistance is common. 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. 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 function 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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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.6 Immunology; 1.6.214 PD-1
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology
ESI research areas: Molecular Biology & Genetics

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Title: Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade
Creators: Joseph L Benci - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Bihui Xu - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Yu Qiu - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Tony J Wu - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hannah Dada - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Christina Twyman-Saint Victor - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Lisa Cucolo - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
David S M Lee - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Kristen E Pauken - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Alexander C Huang - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Tara C Gangadhar - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Ravi K Amaravadi - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Lynn M Schuchter - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Michael D Feldman - Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Hemant Ishwaran - Division of Biostatistics, Department of Epidemiology and Public Health, University of Miami, Miami, FL 33136, USA
Robert H Vonderheide - Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Amit Maity - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
E John Wherry - Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
Andy J Minn - Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: andyminn@mail.med.upenn.edu
Publication Details: Cell (Cambridge), Vol.167(6), pp.1540-1554.e12
Publisher: United States
Grant note: P01 AI112521 / NIAID NIH HHS U19 AI082630 / NIAID NIH HHS R01 AI105343 / NIAID NIH HHS U01 AI095608 / NIAID NIH HHS UL1 TR000460 / NCATS NIH HHS P30 CA016520 / NCI NIH HHS P50 CA174523 / NCI NIH HHS R01 CA163739 / NCI NIH HHS R01 CA158186 / NCI NIH HHS R01 CA172651 / NCI NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Public Health Sciences Research
Language: English
Resource Type: Journal article
PMID: 27912061
PMCID: PMC5385895
Record Identifier: 991031562326402976