Response to immune checkpoint blockade improved in pre-clinical model of breast cancer after bariatric surgery
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Curated by eLife
Evaluation Summary:
This study investigates on how weight loss by bariatric surgery or weight-matched dietary intervention impairs breast cancer growth as well as immunotherapy. This study can potentially provide some therapeutic intervention strategies on combining vertical sleeve gastrectomy and immunotherapy in treating breast cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Bariatric surgery is a sustainable weight loss approach, including vertical sleeve gastrectomy (VSG). Obesity exacerbates tumor growth, while diet-induced weight loss impairs progression. It remains unknown how bariatric surgery-induced weight loss impacts cancer progression or alters response to therapy. Using a pre-clinical model of obesity followed by VSG or diet-induced weight loss, breast cancer progression and immune checkpoint blockade therapy were investigated. Weight loss by VSG or weight-matched dietary intervention before tumor engraftment protected against obesity-exacerbated tumor progression. However, VSG was not as effective as diet in reducing tumor burden despite achieving similar weight and adiposity loss. Leptin did not associate with changes in tumor burden; however, circulating IL-6 was elevated in VSG mice. Uniquely, VSG tumors displayed elevated inflammation and immune checkpoint ligand PD-L1+ myeloid and non-immune cells. VSG tumors also had reduced T lymphocytes and markers of cytolysis, suggesting an ineffective anti-tumor microenvironment which prompted investigation of immune checkpoint blockade. 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. Finally, we compared transcriptomic changes in adipose tissue after bariatric surgery from patients and mouse models. A conserved b ariatric s urgery- a ssociated weight loss s ignature (BSAS) was identified which significantly associated with decreased tumor volume. Findings demonstrate conserved impacts of obesity and bariatric surgery-induced weight loss pathways associated with breast cancer progression.
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Author Response
Reviewer #1 (Public Review):
This study provides relatively convincing in vivo phenotype data in mice related to vertical sleeve gastrectomy (VSG) and provides some potential mechanistic insight. This study can potentially provide some therapeutic intervention strategies on combining VSG and immunotherapy in treating breast cancer. On the other hand, this paper also has some weaknesses especially related to the detailed molecular mechanism and characterization as described below:
- The major weakness lies on the detailed characterization on which inflammatory response factors that may mediate the phenotype of HFS VSG mice when compared to WM Sham mice. The data presented currently is mainly limited to RNA-Seq data, which lacks detailed characterization.
Thank you for your comments which we have addressed and have …
Author Response
Reviewer #1 (Public Review):
This study provides relatively convincing in vivo phenotype data in mice related to vertical sleeve gastrectomy (VSG) and provides some potential mechanistic insight. This study can potentially provide some therapeutic intervention strategies on combining VSG and immunotherapy in treating breast cancer. On the other hand, this paper also has some weaknesses especially related to the detailed molecular mechanism and characterization as described below:
- The major weakness lies on the detailed characterization on which inflammatory response factors that may mediate the phenotype of HFS VSG mice when compared to WM Sham mice. The data presented currently is mainly limited to RNA-Seq data, which lacks detailed characterization.
Thank you for your comments which we have addressed and have strengthened the manuscript. To address your concern, we have quantified IL-6 in plasma which is significantly elevated in HFD- VSG vs WM-Sham. This data is now included as new Figure 3E. IL-6 signaling increases PD-L1 stability (Chan, Li et al. 2019, Li, Zhang et al. 2020). We show in new figure 3F that IL-6 treatment in vitro increased PD-L1 protein in breast cancer cells, as measured by flow cytometry mean fluorescence intensity. We also included new GSEA identification of the hallmark IL6 pathway, which we present as new figure 3G. Therefore, IL-6 is a potential inflammatory response factor that may mediate the phenotype of HFS VSG mice when compared to WM Sham mice. We have included this novel plasma and in vitro data in the abstract, methods, results, and added citations and discussion about IL-6 and PD-L1 stability in the discussion.
- The other significant weakness also is related to the descriptive nature on characterizing the effect of immune features in Fig.4 for these mice. What is the potential mechanism on regulating T cell signaling or Cytolysis in HFS VSG mice vs WM sham mice? This at least needs some preliminary exploration and characterization.
We appreciate your insight. To examine the potential mechanisms known to impact T cell signaling and activation (such as elevated cytolysis markers including granzymes), we examined immune cells that impair T cell activation by additional flow cytometric analysis. We now demonstrate that in HFD-VSG tumors, there is a unique VSG-specific elevation of PD-L1+ monocytic myeloid derived suppressor cells (M-MDSC) and PD-L1+ macrophages relative to all other diet and surgical groups. Compared to HFD-VSG tumors, M-MDSC displayed a significant 2.9-fold reduction in tumor content compared to the WM-Sham group. Similarly, compared to HFD-VSG tumors, PD-L1+ macrophages displayed a significant 1.76-fold reduction in tumor content compared to the WM-Sham group. This is important because PD-L1+ is a marker of immunosuppressive capacity in M-MDSCs and macrophages which would impair T cell activation. This novel data is now included as new Figure 4G-H. We have included details in the methods, results, and added citations and discussion about PD-L1 positivity on M-MDSCs and macrophages in the discussion.
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Evaluation Summary:
This study investigates on how weight loss by bariatric surgery or weight-matched dietary intervention impairs breast cancer growth as well as immunotherapy. This study can potentially provide some therapeutic intervention strategies on combining vertical sleeve gastrectomy and immunotherapy in treating breast cancer.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
This study provides relatively convincing in vivo phenotype data in mice related to vertical sleeve gastrectomy (VSG) and provides some potential mechanistic insight. This study can potentially provide some therapeutic intervention strategies on combining VSG and immunotherapy in treating breast cancer. On the other hand, this paper also has some weaknesses especially related to the detailed molecular mechanism and characterization as described below:
1. The major weakness lies on the detailed characterization on which inflammatory response factors that may mediate the phenotype of HFS VSG mice when compared to WM Sham mice. The data presented currently is mainly limited to RNA-Seq data, which lacks detailed characterization.
2. The other significant weakness also is related to the descriptive nature on …Reviewer #1 (Public Review):
This study provides relatively convincing in vivo phenotype data in mice related to vertical sleeve gastrectomy (VSG) and provides some potential mechanistic insight. This study can potentially provide some therapeutic intervention strategies on combining VSG and immunotherapy in treating breast cancer. On the other hand, this paper also has some weaknesses especially related to the detailed molecular mechanism and characterization as described below:
1. The major weakness lies on the detailed characterization on which inflammatory response factors that may mediate the phenotype of HFS VSG mice when compared to WM Sham mice. The data presented currently is mainly limited to RNA-Seq data, which lacks detailed characterization.
2. The other significant weakness also is related to the descriptive nature on characterizing the effect of immune features in Fig.4 for these mice. What is the potential mechanism on regulating T cell signaling or Cytolysis in HFS VSG mice vs WM sham mice? This at least needs some preliminary exploration and characterization. -
Reviewer #2 (Public Review):
This is a study based on the clinical observation that bariatric surgery in patients appears to be beneficial to reduce breast cancer risk. In mice with diet-induced obesity, followed by vertical sleeve gastrectomy (VSG) or dietary weight loss, tumor graft growth and response to immune checkpoint blockade were investigated. Bariatric surgery was found to be not as effective as dietary interventions in suppressing tumor growth despite achieving a similar extent of weight and adiposity loss. Leptin-mediated signaling was ruled out as a potential mechanism that could account for that difference. Notably, tumors in mice that received VSG displayed elevated inflammation and expression of the immune checkpoint ligand, PD-L1. In addition, mice that received VSG had reduced tumor-infiltrating T lymphocytes and …
Reviewer #2 (Public Review):
This is a study based on the clinical observation that bariatric surgery in patients appears to be beneficial to reduce breast cancer risk. In mice with diet-induced obesity, followed by vertical sleeve gastrectomy (VSG) or dietary weight loss, tumor graft growth and response to immune checkpoint blockade were investigated. Bariatric surgery was found to be not as effective as dietary interventions in suppressing tumor growth despite achieving a similar extent of weight and adiposity loss. Leptin-mediated signaling was ruled out as a potential mechanism that could account for that difference. Notably, tumors in mice that received VSG displayed elevated inflammation and expression of the immune checkpoint ligand, PD-L1. In addition, mice that received VSG had reduced tumor-infiltrating T lymphocytes and cytolysis suggesting an ineffective anti-tumor microenvironment. Anti-PD-L1 immunotherapy suppressed tumor progression after VSG but not in control obese mice. Genomic analysis of adipose tissue after bariatric surgery from both patients and mouse models revealed a conserved gene expression signature.
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Reviewer #3 (Public Review):
In this manuscript, the authors have investigated how weight loss by bariatric surgery or weight-matched dietary intervention impairs breast cancer growth. They have shown that post-bariatric surgery, the tumors show augmented inflammation and an immune checkpoint; PD-L1 expression, which suppresses the anti-tumor immune responses. In addition, anti-PD-L1 therapy in these mice has shown to be more effective at slowing tumor growth. The authors report interesting observations, and the findings are well supported by the data, however, the use of only one syngeneic model tampers the reviewer's enthusiasm. Overall, the study is clinically important and helps in stratifying obese breast cancer patients that may respond to anti-PD-L1 immune checkpoint inhibition.
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