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; 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.

doi:10.1084/jem.20131219

Cited by 130 publications

(146 citation statements)

References 61 publications

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“…These data are different to others who have reported decreased cytokine secretion from elderly macrophages (Corsini et al 1999;Wallace et al 1995). However, a recent conflicting study also showed that macrophages from aged mice produce higher cytokine levels (TNF and IL-6) following in vitro LPS stimulation (Bouchlaka et al 2013). This discrepancy may reflect different technologies, different mouse strains or species, and/or macrophages from different tissue sites; the latter highlighted in a study showing that LPSstimulated splenic macrophages, but not bone marrowderived macrophages, from aging mice demonstrated an aberrant response (Mahbub et al 2012).…”

Section: Discussioncontrasting

confidence: 60%

“…Our data showed that use of an IL-2/anti-CD40 Ab-based immunotherapy could be effective in elderly cancer-bearing hosts. However, a recent study showed that systemic IL-2/anti-CD40 Ab induces rapid and lethal toxicity in aged mice, mediated by pro-inflammatory macrophages (Bouchlaka et al 2013). Our previous studies observed high lethality in young mice treated systemically with IL-2/anti-CD40 Ab (Jackaman et al 2008).…”

Section: Discussionmentioning

confidence: 91%

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IL-2/CD40-activated macrophages rescue age and tumor-induced T cell dysfunction in elderly mice

Jackaman

Dye

Nelson

2014

AGE

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The role of macrophages and their interactions with T cells during aging is not well understood. We determined if activating elderly-derived macrophages could rescue age-related and tumor-induced T cell dysfunction. Healthy elderly (18-24 months) Balb/c contained significantly more splenic IL-10-secreting M2-macrophages and myeloid-derived suppressor cells than young (6-8 weeks) mice. Exposure to syngeneic mesothelioma or lung carcinoma-conditioned media polarized peritoneal macrophages into suppressive M2-macrophages regardless of age. Tumor-exposed, elderly, but not young-derived, macrophages produced high levels of IL-4 and could not induce T cell IFN-γ production. We attempted to rescue tumor-exposed macrophages with LPS/IFN-γ (M1 stimulus) or IL-2/agonist anti-CD40 antibody. Tumor-exposed, M1-stimulated macrophages retained high CD40 expression, yet TNF-α and IFN-γ production were diminished relative to non-tumor-exposed, M1-stimulated controls. These macrophages induced young and elderly-derived T cell proliferation however, T cells did not secrete IFN-γ. In contrast, tumor-exposed, IL-2/CD40-stimulated macrophages rescued elderly-derived T cell IFN-γ production, suggesting that IL-2/CD40-activated macrophages could rescue T cell immunity in aging hosts.

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Section: Discussioncontrasting

confidence: 60%

Section: Discussionmentioning

confidence: 91%

IL-2/CD40-activated macrophages rescue age and tumor-induced T cell dysfunction in elderly mice

Jackaman

Dye

Nelson

2014

AGE

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“…Only when both antigens are present does sustained T cell priming and activation occur. antibody is more toxic in aged mice and mice with obesity 76 . Treatment with etanercept to block TNF in young, obese mice receiving the same immunotherapy prevented the toxic effects of cytokine storm 77 .…”

Section: Box 1 Adoptive T Cell Therapymentioning

confidence: 99%

Is autoimmunity the Achilles' heel of cancer immunotherapy?

June

Warshauer

Bluestone

2017

Nat Med

380

308

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“…The majority of laboratory studies using vertebrates are done with young animals which may be appropriate to model the biology of young humans. Conversely, older animals may be more appropriate for studies of human conditions and diseases prevalent in older humans, as suggested in some published work (Bouchlaka et al 2013). However, there are two primary obstacles to such studies: cost and time.…”

Section: Current Activitiesmentioning

confidence: 99%

Geroscience and the trans-NIH Geroscience Interest Group, GSIG

2017

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Age is by far the major risk factor for most chronic diseases. This has been common knowledge since time immemorial. Aging encompasses the biological changes most often seen as declines of function and increasing burden of disease. The close linkage of these two has led people to believe that aging, like age, is immutable. It is only recently that research into the basic molecular and cellular mechanisms of aging has led to potential interventions that increase lifespan and appear to increase healthspan, as well. Geroscience is an interdisciplinary field that aims to understand the relationship between the biology of aging and the biology of age-related diseases. The Bgeroscience hypothesisp osits that manipulation of aging will delay (in parallel) the appearance or severity of many chronic diseases because these diseases share the same underlying major risk factor (age). The hope is that this will lead to health improvements in the older population with perhaps greater efficiency than can be achieved through the successful cure and management of diseases of aging as they arise individually or as comorbidities.With those concepts in mind, the Geroscience Interest Group (GSIG) was launched as a trans-institute interest group within the NIH in November 2012. Here, we discuss the genesis of the trans-NIH group and the most salient activities that have occurred in the last 5 years.

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Aging predisposes to acute inflammatory induced pathology after tumor immunotherapy

Abstract: Aging strongly promotes inflammation responses, which may predispose individuals after cancer therapies to lethal system toxicities and pathology that can be partially prevented by TNF blockade.

Cited by 130 publications

References 61 publications

IL-2/CD40-activated macrophages rescue age and tumor-induced T cell dysfunction in elderly mice

IL-2/CD40-activated macrophages rescue age and tumor-induced T cell dysfunction in elderly mice

Is autoimmunity the Achilles' heel of cancer immunotherapy?

Geroscience and the trans-NIH Geroscience Interest Group, GSIG

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