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.
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Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgeryDryad Digital Repository, doi:10.5061/dryad.w0vt4b8tq.
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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.
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.
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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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
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Background:
Cervical adenocarcinoma (ADC) is more aggressive compared to other types of cervical cancer (CC), such as squamous cell carcinoma (SCC). The tumor immune microenvironment (TIME) and tumor heterogeneity are recognized as pivotal factors in cancer progression and therapy. However, the disparities in TIME and heterogeneity between ADC and SCC are poorly understood.
Methods:
We performed single-cell RNA sequencing on 11 samples of ADC tumor tissues, with other 4 SCC samples served as controls. The immunochemistry and multiplexed immunofluorescence were conducted to validate our findings.
Results:
Compared to SCC, ADC exhibited unique enrichments in several sub-clusters of epithelial cells with elevated stemness and hyper-malignant features, including the Epi_10_CYSTM1 cluster. ADC displayed a highly immunosuppressive environment characterized by the enrichment of regulatory T cells (Tregs) and tumor-promoting neutrophils. The Epi_10_CYSTM1 cluster recruits Tregs via ALCAM-CD6 signaling, while Tregs reciprocally induce stemness in the Epi_10_CYSTM1 cluster through TGFβ signaling. Importantly, our study revealed that the Epi_10_CYSTM1 cluster could serve as a valuable predictor of lymph node metastasis for CC patients.
Conclusions:
This study highlights the significance of ADC-specific cell clusters in establishing a highly immunosuppressive microenvironment, ultimately contributing to the heightened aggressiveness and poorer prognosis of ADC compared to SCC.
Funding:
Funded by the National Natural Science Foundation of China (82002753; 82072882; 81500475) and the Natural Science Foundation of Hunan Province (2021JJ40324; 2022JJ70103).
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