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

60 Citations (Scopus)

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

Fingerprint

Immunotherapy
Pathology
Neoplasms
Macrophages
Cytokines
Survival
Therapeutic Uses
Knockout Mice
Natural Killer Cells
Volunteers
Immunization
Interleukin-6
Morbidity
T-Lymphocytes
Liver
Population

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Bouchlaka, M. N., Sckisel, G. D., Chen, M., Mirsoian, A., Zamora, A. E., Maverakis, E., ... 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

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

In: Journal of Experimental Medicine, Vol. 210, No. 11, 01.10.2013, p. 2223-2237.

Research output: Contribution to journalArticle

Bouchlaka, MN, Sckisel, GD, Chen, M, Mirsoian, A, Zamora, AE, Maverakis, E, Wilkins, DEC, Alderson, KL, Hsiao, HH, Weiss, JM, Monjazeb, AM, Hesdorffer, C, Ferrucci, L, Longo, DL, Blazar, BR, Wiltrout, RH, Redelman, D, Taub, DD & Murphy, WJ 2013, 'Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy', Journal of Experimental Medicine, vol. 210, no. 11, pp. 2223-2237. https://doi.org/10.1084/jem.20131219
Bouchlaka, Myriam N. ; Sckisel, Gail D. ; Chen, Mingyi ; Mirsoian, Annie ; Zamora, Anthony E. ; Maverakis, Emanual ; Wilkins, Danice E.C. ; Alderson, Kory L. ; Hsiao, Hui Hua ; Weiss, Jonathan M. ; Monjazeb, Arta M. ; Hesdorffer, Charles ; Ferrucci, Luigi ; Longo, Dan L. ; Blazar, Bruce R. ; Wiltrout, Robert H. ; Redelman, Doug ; Taub, Dennis D. ; Murphy, William J. / Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy. In: Journal of Experimental Medicine. 2013 ; Vol. 210, No. 11. pp. 2223-2237.
@article{edf0af044ba641529c3c998fedcfd8b7,
title = "Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy",
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.",
author = "Bouchlaka, {Myriam N.} and Sckisel, {Gail D.} and Mingyi Chen and Annie Mirsoian and Zamora, {Anthony E.} and Emanual Maverakis and Wilkins, {Danice E.C.} and Alderson, {Kory L.} and Hsiao, {Hui Hua} and Weiss, {Jonathan M.} and Monjazeb, {Arta M.} and Charles Hesdorffer and Luigi Ferrucci and Longo, {Dan L.} and Blazar, {Bruce R.} and Wiltrout, {Robert H.} and Doug Redelman and Taub, {Dennis D.} and Murphy, {William J.}",
year = "2013",
month = "10",
day = "1",
doi = "10.1084/jem.20131219",
language = "English (US)",
volume = "210",
pages = "2223--2237",
journal = "Journal of Experimental Medicine",
issn = "0022-1007",
publisher = "Rockefeller University Press",
number = "11",

}

TY - JOUR

T1 - Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

AU - Bouchlaka, Myriam N.

AU - Sckisel, Gail D.

AU - Chen, Mingyi

AU - Mirsoian, Annie

AU - Zamora, Anthony E.

AU - Maverakis, Emanual

AU - Wilkins, Danice E.C.

AU - Alderson, Kory L.

AU - Hsiao, Hui Hua

AU - Weiss, Jonathan M.

AU - Monjazeb, Arta M.

AU - Hesdorffer, Charles

AU - Ferrucci, Luigi

AU - Longo, Dan L.

AU - Blazar, Bruce R.

AU - Wiltrout, Robert H.

AU - Redelman, Doug

AU - Taub, Dennis D.

AU - Murphy, William J.

PY - 2013/10/1

Y1 - 2013/10/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84885783438&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84885783438&partnerID=8YFLogxK

U2 - 10.1084/jem.20131219

DO - 10.1084/jem.20131219

M3 - Article

VL - 210

SP - 2223

EP - 2237

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

SN - 0022-1007

IS - 11

ER -