Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

Myriam N. Bouchlaka, Gail D. Sckisel, Mingyi Chen, Annie Mirsoian, Anthony E. Zamora, Emanual Maverakis, Danice E.C. Wilkins, Kory L. Alderson, Hui Hua Hsiao, Jonathan M. Weiss, Arta M. Monjazeb, Charles Hesdorffer, Luigi Ferrucci, Dan L. Longo, Bruce R. Blazar, Robert H. Wiltrout, Doug Redelman, Dennis D. Taub, William J. Murphy

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2223-2237
Number of pages15
JournalJournal of Experimental Medicine
Volume210
Issue number11
DOIs
StatePublished - Oct 1 2013

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Bouchlaka, M. N., Sckisel, G. D., Chen, M., Mirsoian, A., Zamora, A. E., Maverakis, E., Wilkins, D. E. C., Alderson, K. L., Hsiao, H. H., Weiss, J. M., Monjazeb, A. M., Hesdorffer, C., Ferrucci, L., Longo, D. L., Blazar, B. R., Wiltrout, R. H., Redelman, D., Taub, D. D., & Murphy, W. J. (2013). Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. Journal of Experimental Medicine, 210(11), 2223-2237. https://doi.org/10.1084/jem.20131219