Abstract

An extensive fibroinflammatory stroma rich in macrophages is a hallmark of pancreatic cancer. In this disease, it is well appreciated that macrophages are immunosuppressive and contribute to the poor response to immunotherapy; however, the mechanisms of immune suppression are complex and not fully understood. Immunosuppressive macrophages are classically defined by expression of the enzyme Arginase 1 (Arg1), which we demonstrated is potently expressed in pancreatic tumor associated macrophages from both human patients and mouse models. While routinely used as a polarization marker, Arg1 also catabolizes arginine, an amino acid required for T cell activation and proliferation. To investigate this metabolic function, we used a genetic and a pharmacologic approach to target Arg1 in pancreatic cancer. Genetic inactivation of Arg1 in macrophages, using a dual recombinase genetically engineered mouse model of pancreatic cancer, delayed formation of invasive disease, while increasing CD8+ T cell infiltration. Additionally, Arg1 deletion induced compensatory mechanisms, including Arg1 overexpression in epithelial cells, namely Tuft cells, and Arg2 overexpression in a subset of macrophages. To overcome these compensatory mechanisms, we used a pharmacological approach to inhibit arginase. Treatment of established tumors with the arginase inhibitor CB-1158 exhibited further increased CD8+ T cell infiltration, beyond that seen with the macrophage-specific knockout, and sensitized the tumors to anti-PD1 immune checkpoint blockade. Our data demonstrate that Arg1 drives immune suppression in pancreatic cancer by depleting Arginine and inhibiting T cell activation.

Data availability

Human sc-RNA-seq data was previously published (N. G. Steele et al., 2020) and both raw and processed data are available at the NIH dbGap database accession number phs002071.v1.p1. Raw and processed sc-RNA-seq data for the WT and KPC were previously published and are available at GEO accession number GSM5011580 and GSE202651. Raw and processed sc-RNA-seq data for the KF and KFCA are available at GEO accession number GSE203016.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Rosa Elena Menjivar

    Cellular and Molecular Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  2. Zeribe C Nwosu

    Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  3. Wenting Du

    Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  4. Katelyn L Donahue

    Cancer Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  5. Hanna S Hong

    Department of Immunology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  6. Carlos Espinoza

    Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  7. Kristee Brown

    Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  8. Ashley Velez-Delgado

    Department of Cell and Developmental Biology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  9. Wei Yan

    Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  10. Fatima Lima

    Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  11. Allison Bischoff

    Cancer Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5119-5272
  12. Padma Kadiyala

    Department of Immunology, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  13. Daniel Salas-Escabillas

    Cancer Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0819-989X
  14. Howard C Crawford

    Henry Ford Pancreatic Cancer Center, Detroit, United States
    Competing interests
    No competing interests declared.
  15. Filip Bednar

    Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  16. Eileen Carpenter

    Department of Molecular Biology and Biochemistry, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6775-6943
  17. Yaqing Zhang

    Department of Surgery, University of Michigan-Ann Arbor, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  18. Christopher J Halbrook

    Department of Molecular Biology and Biochemistry, University of California, Irvine, Ann Arbor, United States
    Competing interests
    No competing interests declared.
  19. Costas A Lyssiotis

    Department of Molecular and Integrative Physiology, University of Michigan-Ann Arbor, Ann Arbor, United States
    For correspondence
    clyssiot@umich.edu
    Competing interests
    Costas A Lyssiotis, has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach (US Patent No: 2015126580-A1, 05/07/2015; US Patent No: 20190136238, 05/09/2019; International Patent No: WO2013177426-A2, 04/23/2015)..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9309-6141
  20. Marina Pasca di Magliano

    Cellular and Molecular Biology Program, University of Michigan-Ann Arbor, Ann Arbor, United States
    For correspondence
    marinapa@umich.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9632-9035

Funding

National Institutes of Health (T32-GM007315)

  • Rosa Elena Menjivar

National Cancer Institute (R01-CA244931)

  • Costas A Lyssiotis

National Cancer Institute (R01-CA247516)

  • Howard C Crawford

University of Michigan (Postdoctoral Pioneer Program)

  • Zeribe C Nwosu

University of Michigan (Training Program in Organogenesis)

  • Wenting Du

National Cancer Institute (T32-CA009676)

  • Katelyn L Donahue

National Cancer Institute (T32-AI007413)

  • Hanna S Hong

National Institute of Diabetes and Digestive and Kidney Diseases (T32-DK094775)

  • Hanna S Hong

National Cancer Institute (F31-CA247037)

  • Ashley Velez-Delgado

National Institute of General Medical Sciences (T32-GM008353)

  • Ashley Velez-Delgado

National Institutes of Health (T32-AI007413)

  • Padma Kadiyala

National Cancer Institute (F31-CA257533)

  • Rosa Elena Menjivar

National Cancer Institute (T32-CA009676)

  • Daniel Salas-Escabillas

American College of Gastroenterology (T32-DK094775)

  • Eileen Carpenter

National Cancer Institute (R50-CA232985)

  • Yaqing Zhang

National Cancer Institute (F32-CA228328)

  • Christopher J Halbrook

National Institutes of Health (R00-CA241357)

  • Christopher J Halbrook

National Institutes of Health (T32-HD007505)

  • Rosa Elena Menjivar

University of Michigan (Rackham Merit Fellowship)

  • Rosa Elena Menjivar

National Institutes of Health (U01-CA224145)

  • Marina Pasca di Magliano

National Institutes of Health (R01-CA151588)

  • Marina Pasca di Magliano

National Cancer Institute (R01-CA198074)

  • Marina Pasca di Magliano

National Cancer Institute (R37-CA237421)

  • Costas A Lyssiotis

National Cancer Institute (R01-CA248160)

  • Costas A Lyssiotis

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Gina M DeNicola, Moffitt Cancer Center, United States

Ethics

Animal experimentation: All the animal studies and procedures were conducted in compliance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) at the University of Michigan, protocol number: PRO00009814.

Human subjects: Human research was performed in accordance with the Declaration of Helsinki and the ethical standards and guidelines approved by the University of Michigan Institutional Review Board. Patients provided written informed consent.

Version history

  1. Received: June 1, 2022
  2. Preprint posted: June 24, 2022 (view preprint)
  3. Accepted: January 30, 2023
  4. Accepted Manuscript published: February 2, 2023 (version 1)
  5. Version of Record published: June 12, 2023 (version 2)

Copyright

© 2023, Menjivar et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Rosa Elena Menjivar
  2. Zeribe C Nwosu
  3. Wenting Du
  4. Katelyn L Donahue
  5. Hanna S Hong
  6. Carlos Espinoza
  7. Kristee Brown
  8. Ashley Velez-Delgado
  9. Wei Yan
  10. Fatima Lima
  11. Allison Bischoff
  12. Padma Kadiyala
  13. Daniel Salas-Escabillas
  14. Howard C Crawford
  15. Filip Bednar
  16. Eileen Carpenter
  17. Yaqing Zhang
  18. Christopher J Halbrook
  19. Costas A Lyssiotis
  20. Marina Pasca di Magliano
(2023)
Arginase 1 is a key driver of immune suppression in pancreatic cancer
eLife 12:e80721.
https://doi.org/10.7554/eLife.80721

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https://doi.org/10.7554/eLife.80721

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