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Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice.

Authors
  • Mirsoian, Annie1
  • Bouchlaka, Myriam N1
  • Sckisel, Gail D1
  • Chen, Mingyi1
  • Pai, Chien-Chun Steven1
  • Maverakis, Emanuel1
  • Spencer, Richard G2
  • Fishbein, Kenneth W2
  • Siddiqui, Sana2
  • Monjazeb, Arta M1
  • Martin, Bronwen2
  • Maudsley, Stuart2
  • Hesdorffer, Charles2
  • Ferrucci, Luigi2
  • Longo, Dan L2
  • Blazar, Bruce R3
  • Wiltrout, Robert H4
  • Taub, Dennis D5
  • Murphy, William J6
  • 1 Department of Dermatology, Department of Pathology and Laboratory Medicine, Department of Radiation Oncology, and Department of Dermatology and Internal Medicine, University of California, Davis, Sacramento, CA 95817.
  • 2 National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
  • 3 Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455.
  • 4 National Cancer Institute, Frederick, MD 21702.
  • 5 Department of Dermatology, Department of Pathology and Laboratory Medicine, Department of Radiation Oncology, and Department of Dermatology and Internal Medicine, University of California, Davis, Sacramento, CA 95817 Hematology and Immunology Translational Research Center, VA Medical Center, Washington, DC 20422.
  • 6 Department of Dermatology, Department of Pathology and Laboratory Medicine, Department of Radiation Oncology, and Department of Dermatology and Internal Medicine, University of California, Davis, Sacramento, CA 95817 [email protected]
Type
Published Article
Journal
Journal of Experimental Medicine
Publisher
The Rockefeller University Press
Publication Date
Nov 17, 2014
Volume
211
Issue
12
Pages
2373–2383
Identifiers
DOI: 10.1084/jem.20140116
PMID: 25366964
Source
Medline
License
Unknown

Abstract

Aging is a contributing factor in cancer occurrence. We recently demonstrated that systemic immunotherapy (IT) administration in aged, but not young, mice resulted in induction of rapid and lethal cytokine storm. We found that aging was accompanied by increases in visceral fat similar to that seen in young obese (ob/ob or diet-induced obese [DIO]) mice. Yet, the effects of aging and obesity on inflammatory responses to immunotherapeutics are not well defined. We determine the effects of adiposity on systemic IT tolerance in aged compared with young obese mice. Both young ob/ob- and DIO-generated proinflammatory cytokine levels and organ pathologies are comparable to those in aged ad libitum mice after IT, culminating in lethality. Young obese mice exhibited greater ratios of M1/M2 macrophages within the peritoneal and visceral adipose tissues and higher percentages of TNF(+) macrophages in response to αCD40/IL-2 as compared with young lean mice. Macrophage depletion or TNF blockade in conjunction with αCD40/IL-2 prevented cytokine storms in young obese mice and protected from lethality. Calorie-restricted aged mice contain less visceral fat and displayed reduced cytokine levels, protection from organ pathology, and protection from lethality upon αCD40/IL-2 administration. Our data demonstrate that adiposity is a critical factor in the age-associated pathological responses to systemic anti-cancer IT.

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