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Pingili AK, Chaib M, Sipe LM, et al. Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer. Cell Rep. 2021;35(12):109285doi: 10.1016/j.celrep.2021.109285.
Pingili, A. K., Chaib, M., Sipe, L. M., Miller, E. J., Teng, B., Sharma, R., Yarbro, J. R., Asemota, S., Al Abdallah, Q., Mims, T. S., Marion, T. N., Daria, D., Sekhri, R., Hamilton, A. M., Troester, M. A., Jo, H., Choi, H. Y., Hayes, D. N., Cook, K. L., Narayanan, R., Pierre, J. F., & Makowski, L. (2021). Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer. Cell reports, 35(12), 109285. https://doi.org/10.1016/j.celrep.2021.109285
Pingili, Ajeeth K, et al. "Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer." Cell reports vol. 35,12 (2021): 109285. doi: https://doi.org/10.1016/j.celrep.2021.109285
Pingili AK, Chaib M, Sipe LM, Miller EJ, Teng B, Sharma R, Yarbro JR, Asemota S, Al Abdallah Q, Mims TS, Marion TN, Daria D, Sekhri R, Hamilton AM, Troester MA, Jo H, Choi HY, Hayes DN, Cook KL, Narayanan R, Pierre JF, Makowski L. Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer. Cell Rep. 2021 Jun 22;35(12):109285. doi: 10.1016/j.celrep.2021.109285. PMID: 34161764; PMCID: PMC8574993.
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Cell Rep. 2021 Jun 22;35(12):109285. doi: 10.1016/j.celrep.2021.109285.

Immune checkpoint blockade reprograms systemic immune landscape and tumor microenvironment in obesity-associated breast cancer.

Cell reports

Ajeeth K Pingili, Mehdi Chaib, Laura M Sipe, Emily J Miller, Bin Teng, Rahul Sharma, Johnathan R Yarbro, Sarah Asemota, Qusai Al Abdallah, Tahliyah S Mims, Tony N Marion, Deidre Daria, Radhika Sekhri, Alina M Hamilton, Melissa A Troester, Heejoon Jo, Hyo Young Choi, D Neil Hayes, Katherine L Cook, Ramesh Narayanan, Joseph F Pierre, Liza Makowski

Affiliations

  1. Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  2. Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  3. Department of Pediatrics, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  4. Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Office of Vice Chancellor for Research, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  5. Office of Vice Chancellor for Research, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  6. Department of Pathology, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  7. Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
  8. Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC 27599, USA; Department of Pathology and Laboratory Medicine, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
  9. Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; UTHSC Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA.
  10. Department of Surgery, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA.
  11. Department of Pediatrics, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: [email protected].
  12. Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA; UTHSC Center for Cancer Research, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN 38163, USA. Electronic address: [email protected].

PMID: 34161764 PMCID: PMC8574993 DOI: 10.1016/j.celrep.2021.109285

Abstract

Immune checkpoint blockade (ICB) has improved outcomes in some cancers. A major limitation of ICB is that most patients fail to respond, which is partly attributable to immunosuppression. Obesity appears to improve immune checkpoint therapies in some cancers, but impacts on breast cancer (BC) remain unknown. In lean and obese mice, tumor progression and immune reprogramming were quantified in BC tumors treated with anti-programmed death-1 (PD-1) or control. Obesity augments tumor incidence and progression. Anti-PD-1 induces regression in lean mice and potently abrogates progression in obese mice. BC primes systemic immunity to be highly responsive to obesity, leading to greater immunosuppression, which may explain greater anti-PD-1 efficacy. Anti-PD-1 significantly reinvigorates antitumor immunity despite persistent obesity. Laminin subunit beta-2 (Lamb2), downregulated by anti-PD-1, significantly predicts patient survival. Lastly, a microbial signature associated with anti-PD-1 efficacy is identified. Thus, anti-PD-1 is highly efficacious in obese mice by reinvigorating durable antitumor immunity. VIDEO ABSTRACT.

Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.

Keywords: MDSC; TAM; adiposity; high-fat diet; immunosuppression; immunotherapy; mammary fat pad; metainflammation; microbiome; myeloid-derived suppressor cell; triple-negative breast cancer; tumor-associated macrophage

Conflict of interest statement

Declaration of interests The authors declare no competing interests.

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