Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

Lawrence P. Andrews; Ashwin Somasundaram; Jessica M. Moskovitz; Andrea L. Szymczak-Workman; Chang Liu; Anthony R. Cillo; Huang Lin; Daniel P. Normolle; Kelly D. Moynihan; Ichiro Taniuchi; Darrell J. Irvine; John M. Kirkwood; Evan J. Lipson; Robert L. Ferris; Tullia C. Bruno; Creg J. Workman; Dario A. A. Vignali

doi:10.1126/sciimmunol.abc2728

Research ArticleTUMOR IMMUNOLOGY

Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

View ORCID ProfileLawrence P. Andrews¹,²,³,
View ORCID ProfileAshwin Somasundaram¹,²,³,⁴,
View ORCID ProfileJessica M. Moskovitz¹,²,³,
View ORCID ProfileAndrea L. Szymczak-Workman¹,
View ORCID ProfileChang Liu¹,²,³,
View ORCID ProfileAnthony R. Cillo¹,²,³,
View ORCID ProfileHuang Lin⁵,
View ORCID ProfileDaniel P. Normolle ⁵,
View ORCID ProfileKelly D. Moynihan⁶,⁷,
View ORCID ProfileIchiro Taniuchi⁸,
View ORCID ProfileDarrell J. Irvine ⁶,⁷,⁹,
View ORCID ProfileJohn M. Kirkwood³,⁴,
View ORCID ProfileEvan J. Lipson¹⁰,
Robert L. Ferris²,³,¹¹,
Tullia C. Bruno¹,²,³,
View ORCID ProfileCreg J. Workman¹,²,³ and
View ORCID ProfileDario A. A. Vignali ¹,²,³,*

¹Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
²Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
³Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.
⁴Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁵Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.
⁶Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁸RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.
⁹Howard Hughes Medical Institute, Chevy Chase, MD, USA.
¹⁰Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
¹¹Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

↵*Corresponding author. Email: dvignali{at}pitt.edu

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Science Immunology 17 Jul 2020:
Vol. 5, Issue 49, eabc2728
DOI: 10.1126/sciimmunol.abc2728

Lawrence P. Andrews

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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Ashwin Somasundaram

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

4Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

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Jessica M. Moskovitz

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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Andrea L. Szymczak-Workman

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

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Chang Liu

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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Anthony R. Cillo

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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Huang Lin

5Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.

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Daniel P. Normolle

5Department of Biostatistics, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.

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Kelly D. Moynihan

6Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

7Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

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Ichiro Taniuchi

8RIKEN Center for Integrative Medical Sciences, Yokohama City, Kanagawa, Japan.

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Darrell J. Irvine

6Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA.

7Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.

9Howard Hughes Medical Institute, Chevy Chase, MD, USA.

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John M. Kirkwood

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

4Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

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Evan J. Lipson

10Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, and Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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Robert L. Ferris

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

11Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

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Tullia C. Bruno

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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Creg J. Workman

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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Dario A. A. Vignali

1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

2Tumor Microenvironment Center, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

3Cancer Immunology and Immunotherapy Program, UPMC Hillman Cancer Center, Pittsburgh, PA, USA.

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For correspondence: dvignali@pitt.edu

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Resistance to PD1 blockade in the absence of metalloprotease-mediated LAG3 shedding

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