Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery

Abstract

Bariatric surgery is becoming more prevalent as a sustainable weight loss approach, with vertical sleeve gastrectomy (VSG) being the first line of surgical intervention. We and others have shown that obesity exacerbates tumor growth while diet-induced weight loss impairs obesity-driven progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters responses to therapy. Using a pre-clinical model of diet induced obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy was investigated. Weight loss by bariatric surgery or weight matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as dietary intervention in reducing tumor burden despite achieving a similar extent of weight and adiposity loss. Circulating leptin did not associate with changes in tumor burden, however circulating IL-6 was elevated in mice after VSG. Uniquely, tumors in mice that received VSG displayed elevated inflammation and immune checkpoint ligand PD-L1+ myeloid and non-immune cells. Further, mice that received VSG had reduced tumor T lymphocytes and markers of cytolysis suggesting an ineffective anti-tumor microenvironment. VSG-associated elevation of PD-L1 prompted us to next investigate the efficacy of immune checkpoint blockade in lean, obese, and formerly obese mice that lost weight by VSG or weight matched controls. While obese mice were resistant to immune checkpoint blockade, anti-PD-L1 potently impaired tumor progression after VSG through improved anti-tumor immunity. Thus, in formerly obese mice, surgical weight loss followed by immunotherapy reduced breast cancer burden. Last, we compared transcriptomic changes in adipose tissue after bariatric surgery from both patients and mouse models that revealed a conserved bariatric surgery associated weight loss signature (BSAS). Importantly, BSAS significantly associated with decreased tumor volume. Our findings demonstrate conserved impacts of obesity and bariatric surgery-induced weight loss pathways associated with breast cancer progression.

Data availability

The data generated in this study are available within the source data file stored in Dryad Digital Repository, doi:10.5061/dryad.w0vt4b8tq.The RNA-seq data generated in this study are publicly available in NCBI GEO GSE174760 of tumor RNA-seq and NCBI GEO GSE174761 of mammary fat pad RNA-seq.

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

Article and author information

Author details

  1. Laura M Sipe

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Mehdi Chaib

    Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Emily B Korba

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7422-9084
  4. Heejoon Jo

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Mary Camille Lovely

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Brittany R Counts

    Integrative Muscle Biology Laboratory, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Ubaid Tanveer

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jeremiah R Holt

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Jared C Clements

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Neena A John

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Deidre Daria

    Office of Vice Chancellor for Research, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Tony N Marion

    Office of Vice Chancellor for Research, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Margaret S Bohm

    Department of Microbiology, Immunology, and Biochemistry, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Radhika Sekhri

    Department of Pathology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Ajeeth K Pingili

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Bin Teng

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. James A Carson

    Integrative Muscle Biology Laboratory, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. D Neil Hayes

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  19. Matthew J Davis

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  20. Katherine L Cook

    Department of Surgery, Wake Forest University, Winston Salem, United States
    Competing interests
    The authors declare that no competing interests exist.
  21. Joseph F Pierre

    Department of Microbiology, University of Tennessee Health Science Center, Memphis, United States
    Competing interests
    The authors declare that no competing interests exist.
  22. Liza Makowski

    Department of Medicine, University of Tennessee Health Science Center, Memphis, United States
    For correspondence
    liza.makowski@uthsc.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5337-8037

Funding

National Cancer Institute (R01CA253329)

  • Matthew J Davis
  • Joseph F Pierre
  • Liza Makowski

National Cancer Institute (R37CA226969)

  • D Neil Hayes
  • Liza Makowski

National Cancer Institute (F32 CA250192)

  • Laura M Sipe

National Cancer Institute (R25CA203650)

  • Laura M Sipe

Mary Kay Foundation

  • Liza Makowski

V Foundation for Cancer Research

  • D Neil Hayes

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK127209)

  • Joseph F Pierre

American Association for Cancer Research (Triple Negative Breast Cancer Foundation Research Fellowship)

  • Laura M Sipe

National Cancer Institute (F30CA265224)

  • Jeremiah R Holt

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

Ethics

Animal experimentation: Animal studies were performed with approval and in accordance with the guidelines of the Institutional Animal Care and Use Committee (IACUC) at the University of Tennessee Health Science Center (Animal Welfare Assurance Number A3325-01) and in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals . The protocol was approved under the protocol identifier 21.0224.

Reviewing Editor

  1. Qing Zhang, University of Texas Southwestern Medical Center, United States

Publication history

  1. Received: March 31, 2022
  2. Preprint posted: April 1, 2022 (view preprint)
  3. Accepted: June 26, 2022
  4. Accepted Manuscript published: July 1, 2022 (version 1)
  5. Version of Record published: August 1, 2022 (version 2)

Copyright

© 2022, Sipe 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. Laura M Sipe
  2. Mehdi Chaib
  3. Emily B Korba
  4. Heejoon Jo
  5. Mary Camille Lovely
  6. Brittany R Counts
  7. Ubaid Tanveer
  8. Jeremiah R Holt
  9. Jared C Clements
  10. Neena A John
  11. Deidre Daria
  12. Tony N Marion
  13. Margaret S Bohm
  14. Radhika Sekhri
  15. Ajeeth K Pingili
  16. Bin Teng
  17. James A Carson
  18. D Neil Hayes
  19. Matthew J Davis
  20. Katherine L Cook
  21. Joseph F Pierre
  22. Liza Makowski
(2022)
Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery
eLife 11:e79143.
https://doi.org/10.7554/eLife.79143
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