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

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  • Pingili, A.K
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Chaib, M
    • Other Affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Sipe, L.M
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Miller, E.J
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Teng, B
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Sharma, R
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Yarbro, J.R
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Asemota, S
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Al Abdallah, Q
    • Other Affiliation: Department of Pediatrics, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Mims, T.S
    • Other Affiliation: Department of Pediatrics, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Marion, T.N
    • Other Affiliation: Department of Microbiology, Immunology, and Biochemistry, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Daria, D
    • Other Affiliation: Office of Vice Chancellor for Research, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Sekhri, R
    • Other Affiliation: Department of Pathology, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Hamilton, A.M
    • School of Medicine, Department of Pathology and Laboratory Medicine
  • Troester, M.A
    • Gillings School of Global Public Health, Department of Epidemiology
  • Jo, H
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Choi, H.Y
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Hayes, D.N
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Cook, K.L
    • Other Affiliation: Department of Surgery, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston Salem, NC, United States
  • Narayanan, R
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Pierre, J.F
    • Other Affiliation: Department of Pediatrics, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
  • Makowski, L
    • Other Affiliation: Department of Medicine, Division of Hematology and Oncology, Department of Medicine, College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
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.
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • Cell Reports
Journal volume
  • 35
Journal issue
  • 12
Language
  • English
Version
  • Postprint
Funder
  • DOD BCRP W81XWH-20-1-0014
  • National Institute of Environmental Health Sciences, NIEHS: P30ES010126, U01ES019472
  • Harvard Transdisciplinary Research in Energetics and Cancer Center, Harvard University, TREC
  • Triple Negative Breast Cancer Foundation
  • Mary Kay Foundation, MKF
  • National Institutes of Health, NIH
  • V Foundation for Cancer Research, VFCR
  • National Institute of Diabetes and Digestive and Kidney Diseases, NIDDK: R01DK127209
  • Health Science Center, University of Tennessee
  • National Cancer Institute, NCI: F31CA257388, F32CA250192, R01CA229164, R01CA253329, R25CA203650, R37CA226969, U24CA210988, UG1CA233333
  • American Association for Cancer Research, AACR
ISSN
  • 2211-1247
Publisher
  • Elsevier B.V.

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