Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery
- University of Tennessee Health Science Center, United States
- Wake Forest University, United States
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.
-
Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgeryDryad Digital Repository, doi:10.5061/dryad.w0vt4b8tq.
-
Impact of bariatric surgery on RNA-seq gene expression profiles of adipose tissue in humansNCBI Gene Expression Omnibus, GSE65540.
Article and author information
Author details
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.
Reviewing Editor
- Qing Zhang, University of Texas Southwestern Medical Center, United States
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.
Version history
- Received: March 31, 2022
- Preprint posted: April 1, 2022 (view preprint)
- Accepted: June 26, 2022
- Accepted Manuscript published: July 1, 2022 (version 1)
- 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.
Metrics
-
- 970
- views
-
- 230
- downloads
-
- 9
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Cancer Biology
- Cell Biology
Collective cell migration is fundamental for the development of organisms and in the adult, for tissue regeneration and in pathological conditions such as cancer. Migration as a coherent group requires the maintenance of cell-cell interactions, while contact inhibition of locomotion (CIL), a local repulsive force, can propel the group forward. Here we show that the cell-cell interaction molecule, N-cadherin, regulates both adhesion and repulsion processes during rat Schwann cell (SC) collective migration, which is required for peripheral nerve regeneration. However, distinct from its role in cell-cell adhesion, the repulsion process is independent of N-cadherin trans-homodimerisation and the associated adherens junction complex. Rather, the extracellular domain of N-cadherin is required to present the repulsive Slit2/Slit3 signal at the cell-surface. Inhibiting Slit2/Slit3 signalling inhibits CIL and subsequently collective Schwann cell migration, resulting in adherent, nonmigratory cell clusters. Moreover, analysis of ex vivo explants from mice following sciatic nerve injury showed that inhibition of Slit2 decreased Schwann cell collective migration and increased clustering of Schwann cells within the nerve bridge. These findings provide insight into how opposing signals can mediate collective cell migration and how CIL pathways are promising targets for inhibiting pathological cell migration.
-
- Cancer Biology
- Structural Biology and Molecular Biophysics
Abelson tyrosine kinase (Abl) is regulated by the arrangement of its regulatory core, consisting sequentially of the SH3, SH2, and kinase (KD) domains, where an assembled or disassembled core corresponds to low or high kinase activity, respectively. It was recently established that binding of type II ATP site inhibitors, such as imatinib, generates a force from the KD N-lobe onto the SH3 domain and in consequence disassembles the core. Here, we demonstrate that the C-terminal αI-helix exerts an additional force toward the SH2 domain, which correlates both with kinase activity and type II inhibitor-induced disassembly. The αI-helix mutation E528K, which is responsible for the ABL1 malformation syndrome, strongly activates Abl by breaking a salt bridge with the KD C-lobe and thereby increasing the force onto the SH2 domain. In contrast, the allosteric inhibitor asciminib strongly reduces Abl’s activity by fixating the αI-helix and reducing the force onto the SH2 domain. These observations are explained by a simple mechanical model of Abl activation involving forces from the KD N-lobe and the αI-helix onto the KD/SH2SH3 interface.
