Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. J Exp Med 2013 Oct 21;210(11):2223-37
Date
10/02/2013Pubmed ID
24081947Pubmed Central ID
PMC3804937DOI
10.1084/jem.20131219Scopus ID
2-s2.0-84885783438 (requires institutional sign-in at Scopus site) 113 CitationsAbstract
Cancer commonly occurs in the elderly and immunotherapy (IT) is being increasingly applied to this population. However, the majority of preclinical mouse tumor models assessing potential efficacy and toxicities of therapeutics use young mice. We assessed the impact of age on responses to systemic immune stimulation. In contrast to young mice, systemic cancer IT regimens or LPS given to aged mice resulted in rapid and lethal toxicities affecting multiple organs correlating with heightened proinflammatory cytokines systemically and within the parenchymal tissues. This inflammatory response and increased morbidity with age was independent of T cells or NK cells. However, prior in vivo depletion of macrophages in aged mice resulted in lesser cytokine levels, increased survival, and decreased liver histopathology. Furthermore, macrophages from aged mice and normal human elderly volunteers displayed heightened TNF and IL-6 production upon in vitro stimulation. Treatment of both TNF knockout mice and in vivo TNF blockade in aged mice resulted in significant increases in survival and lessened pathology. Importantly, TNF blockade in tumor-bearing, aged mice receiving IT displayed significant anti-tumor effects. These data demonstrate the critical role of macrophages in the age-associated hyper-inflammatory cytokine responses to systemic immunostimulation and underscore the importance of performing preclinical assessments in aged mice.
Author List
Bouchlaka MN, Sckisel GD, Chen M, Mirsoian A, Zamora AE, Maverakis E, Wilkins DE, Alderson KL, Hsiao HH, Weiss JM, Monjazeb AM, Hesdorffer C, Ferrucci L, Longo DL, Blazar BR, Wiltrout RH, Redelman D, Taub DD, Murphy WJAuthor
Anthony E. Zamora PhD Assistant Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AgingAnimals
CD40 Antigens
Cytokines
Dose-Response Relationship, Drug
Female
Humans
Immunotherapy
Inflammation
Inflammation Mediators
Lipopolysaccharides
Liver
Macrophages
Mice
Mice, Inbred C57BL
Neoplasms
Survival Analysis
Tumor Necrosis Factor-alpha
