CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions.

Abstract

The development of pancreatic cancer requires recruitment and activation of different macrophage populations. However, little is known about how macrophages are attracted to the pancreas after injury or an oncogenic event, and how they crosstalk with lesion cells or other cells of the lesion microenvironment. Here, we delineate the importance of CXCL10/CXCR3 signaling during the early phase of murine pancreatic cancer. We show that CXCL10 is produced by pancreatic precancerous lesion cells in response to IFNγ signaling, and that inflammatory macrophages are recipients for this chemokine. CXCL10/CXCR3 signaling in macrophages mediates their chemoattraction to the pancreas, enhances their proliferation and maintains their inflammatory identity. Blocking of CXCL10/CXCR3 signaling in vivo shifts macrophage populations to a tumor promoting (Ym1+, Fizz+, Arg1+) phenotype, increases fibrosis and mediates progression of lesions, highlighting the importance of this pathway in PDA development. This is reversed when CXCL10 is overexpressed in PanIN cells.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data have been included for all Figures and Supplemental Figures.

Article and author information

Author details

  1. Veethika Pandey

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Alicia Fleming-Martinez

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ligia Bastea

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Heike R Doeppler

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jillian Eisenhauer

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Tam Le

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Brandy Edenfield

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Peter Storz

    Cancer Biology, Mayo Clinic, Jacksonville, United States
    For correspondence
    storz.peter@mayo.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0132-5128

Funding

National Cancer Institute (CA229560)

  • Peter Storz

National Cancer Institute (CA200572)

  • Peter Storz

National Cancer Institute (P50CA102701)

  • Peter Storz

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All animal experiments were conducted under IACUC approved protocols (A50214-14-R17, A30615-15-R18) and were run in accordance with institutional guidance and regulation.

Copyright

© 2021, Pandey 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. Veethika Pandey
  2. Alicia Fleming-Martinez
  3. Ligia Bastea
  4. Heike R Doeppler
  5. Jillian Eisenhauer
  6. Tam Le
  7. Brandy Edenfield
  8. Peter Storz
(2021)
CXCL10/CXCR3 signaling contributes to an inflammatory microenvironment and its blockade enhances progression of murine pancreatic precancerous lesions.
eLife 10:e60646.
https://doi.org/10.7554/eLife.60646

Share this article

https://doi.org/10.7554/eLife.60646

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