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

  • Annie Mirsoian
    Department of Dermatology 1 , 2 , 3 , and 4
  • Myriam N. Bouchlaka
    Department of Dermatology 1 , 2 , 3 , and 4
  • Gail D. Sckisel
    Department of Dermatology 1 , 2 , 3 , and 4
  • Mingyi Chen
    Department of Dermatology 1 , 2 , 3 , and 4
  • Chien-Chun Steven Pai
    Department of Dermatology 1 , 2 , 3 , and 4
  • Emanuel Maverakis
    Department of Dermatology 1 , 2 , 3 , and 4
  • Richard G. Spencer
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Kenneth W. Fishbein
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Sana Siddiqui
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Arta M. Monjazeb
    Department of Dermatology 1 , 2 , 3 , and 4
  • Bronwen Martin
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Stuart Maudsley
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Charles Hesdorffer
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Luigi Ferrucci
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Dan L. Longo
    National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224 5
  • Bruce R. Blazar
    Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455 6
  • Robert H. Wiltrout
    National Cancer Institute, Frederick, MD 21702 7
  • Dennis D. Taub
    Department of Dermatology 1 , 2 , 3 , and 4
  • William J. Murphy
    Department of Dermatology 1 , 2 , 3 , and 4

説明

<jats:p>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.</jats:p>

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