Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways

Jessica M. Haverkamp, Amber Smith, Ricardo Weinlich, Christopher P. Dillon, Joseph E. Qualls, Geoffrey Neale, Brian Koss, Young Kim, Vincenzo Bronte, Marco J. Herold, Douglas R. Green, Joseph T. Opferman, Peter J. Murray

Research output: Contribution to journalArticle

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Abstract

Nonresolving inflammation expands a heterogeneous population of myeloid suppressor cells capable of inhibiting Tcell function. This heterogeneity has confounded the functional dissection of individual myeloid subpopulations and presents an obstacle for antitumor immunity and immunotherapy. Using genetic manipulation of cell death pathways, we foundthe monocytic suppressor-cell subset, but not the granulocytic subset, requires continuous c-FLIP expression to prevent caspase-8-dependent, RIPK3-independent cell death. Development of the granulocyte subset requires MCL-1-mediated control of the intrinsic mitochondrial death pathway. Monocytic suppressors tolerate the absence of MCL-1 provided cytokines increase expression of the MCL-1-related protein A1. Monocytic suppressors mediate Tcell suppression, whereas their granulocytic counterparts lack suppressive function. The loss of the granulocytic subset via conditional MCL-1 deletion did not alter tumor incidence implicating the monocytic compartment as the functionally immunosuppressive subset invivo. Thus, death pathway modulation defines the development, survival, and function of myeloid suppressor cells.

Original languageEnglish (US)
Pages (from-to)947-959
Number of pages13
JournalImmunity
Volume41
Issue number6
DOIs
StatePublished - Dec 18 2014

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Myeloid Cells
Cell Death
Caspase 8
Immunosuppressive Agents
Granulocytes
Immunotherapy
Dissection
Immunity
Cytokines
Inflammation
Incidence
Population
Neoplasms
Proteins

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways. / Haverkamp, Jessica M.; Smith, Amber; Weinlich, Ricardo; Dillon, Christopher P.; Qualls, Joseph E.; Neale, Geoffrey; Koss, Brian; Kim, Young; Bronte, Vincenzo; Herold, Marco J.; Green, Douglas R.; Opferman, Joseph T.; Murray, Peter J.

In: Immunity, Vol. 41, No. 6, 18.12.2014, p. 947-959.

Research output: Contribution to journalArticle

Haverkamp, JM, Smith, A, Weinlich, R, Dillon, CP, Qualls, JE, Neale, G, Koss, B, Kim, Y, Bronte, V, Herold, MJ, Green, DR, Opferman, JT & Murray, PJ 2014, 'Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways', Immunity, vol. 41, no. 6, pp. 947-959. https://doi.org/10.1016/j.immuni.2014.10.020
Haverkamp, Jessica M. ; Smith, Amber ; Weinlich, Ricardo ; Dillon, Christopher P. ; Qualls, Joseph E. ; Neale, Geoffrey ; Koss, Brian ; Kim, Young ; Bronte, Vincenzo ; Herold, Marco J. ; Green, Douglas R. ; Opferman, Joseph T. ; Murray, Peter J. / Myeloid-derived suppressor activity is mediated by monocytic lineages maintained by continuous inhibition of extrinsic and intrinsic death pathways. In: Immunity. 2014 ; Vol. 41, No. 6. pp. 947-959.
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