title: Adiposity induces lethal cytokine storm after systemic administration of stimulatory immunotherapy regimens in aged mice.
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.
authors.affiliation: 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.
authors.forename: Annie
authors.initials: A
authors.lastname: Mirsoian
authors.affiliation: 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.
authors.forename: Myriam N
authors.initials: MN
authors.lastname: Bouchlaka
authors.affiliation: 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.
authors.forename: Gail D
authors.initials: GD
authors.lastname: Sckisel
authors.affiliation: 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.
authors.forename: Mingyi
authors.initials: M
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Chien-Chun Steven
authors.initials: CC
authors.lastname: Pai
authors.affiliation: 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.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Maverakis
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Spencer
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Fishbein
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Sana
authors.initials: S
authors.lastname: Siddiqui
authors.affiliation: 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.
authors.forename: Arta M
authors.initials: AM
authors.lastname: Monjazeb
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Charles
authors.initials: C
authors.lastname: Hesdorffer
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.affiliation: National Institute on Aging-Intramural Research Program, National Institutes of Health, Biomedical Research Center, Baltimore, MD 21224.
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
authors.affiliation: Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.affiliation: National Cancer Institute, Frederick, MD 21702.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.affiliation: 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.
authors.forename: Dennis D
authors.initials: DD
authors.lastname: Taub
authors.affiliation: 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 wmjmurphy@ucdavis.edu.
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D050154:Adiposity / Q000276:immunology*; D000375:Aging / Q000276:immunology*; D000818:Animals; D031204:Caloric Restriction; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D018836:Inflammation Mediators / Q000097:blood / Q000276:immunology; D050152:Intra-Abdominal Fat / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009369:Neoplasms / Q000276:immunology / Q000628:therapy; D009765:Obesity / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D014409:Tumor Necrosis Factor-alpha