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

被引：872

作者：

Benci, Joseph L. ^{[1
,7
]}

Xu, Bihui ^{[1
,7
]}

Qiu, Yu ^{[1
,7
]}

Wu, Tony J. ^{[1
,7
]}

Dada, Hannah ^{[1
,7
]}

Twyman-Saint Victor, Christina ^{[2
,7
]}

Cucolo, Lisa ^{[1
,7
]}

Lee, David S. M. ^{[1
,7
]}

Pauken, Kristen E. ^{[3
,5
]}

Huang, Alexander C. ^{[2
,5
]}

Gangadhar, Tara C. ^{[2
]}

Amaravadi, Ravi K. ^{[2
]}

Schuchter, Lynn M. ^{[2
]}

Feldman, Michael D. ^{[4
]}

Ishwaran, Hemant ^{[8
]}

Vonderheide, Robert H. ^{[2
,5
,6
,7
]}

Maity, Amit ^{[1
]}

Wherry, E. John ^{[3
,5
,6
]}

Minn, Andy J. ^{[1
,5
,6
,7
]}

机构：

[1] Univ Penn, Perelman Sch Med, Dept Radiat Oncol, Philadelphia, PA 19104 USA

[2] Univ Penn, Perelman Sch Med, Dept Med, Philadelphia, PA 19104 USA

[3] Univ Penn, Perelman Sch Med, Dept Microbiol, Philadelphia, PA 19104 USA

[4] Univ Penn, Perelman Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[5] Univ Penn, Perelman Sch Med, Inst Immunol, Philadelphia, PA 19104 USA

[6] Univ Penn, Perelman Sch Med, Parker Inst Canc Immunotherapy, Philadelphia, PA 19104 USA

[7] Univ Penn, Perelman Sch Med, Abramson Family Canc Res Inst, Philadelphia, PA 19104 USA

[8] Univ Miami, Dept Epidemiol & Publ Hlth, Div Biostat, Miami, FL 33136 USA

来源：

CELL | 2016年 / 167卷 / 06期

关键词：

CD8(+) T-CELLS; CHRONIC VIRAL-INFECTION; PD-1; BLOCKADE; I INTERFERON; CANCER; THERAPY; EXHAUSTION; RADIATION; RECEPTORS; REJECTION;

D O I：

10.1016/j.cell.2016.11.022

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1540 / +

页数：27

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