Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy

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203 Citations (Scopus)

Abstract

Cancer immunotherapy has focused on inducing and expanding CTLs and improving the immune recognition of weak antigenic determinants expressed by tumors. However, few positive clinical outcomes have been reported due, in part, to tumor-associated immunologic tolerance, supporting the need for an emphasis on overcoming immunosuppression. Systemic immunosuppression is associated with abnormal myelopoiesis secondary to tumor growth, myelosuppressive therapy, and growth factor administration and subsequent expansion/mobilization of bone marrow-derived immunosuppressive cells. These myeloid-derived suppressor cells (MDSC) reduce activated T-cell number and inhibit their function by multiple mechanisms, including depletion of L-arginine by arginase-1 (ARG1) production of nitric oxide, reactive oxygen species, and reactive nitrogen oxide species by inducible nitric oxide synthase. Increased numbers of MDSCs are associated with neoplastic, inflammatory, infectious, and graft-versus-host diseases where they restrain exuberant or novel T-cell responses. In this review, we discuss critical components of MDSC-mediated suppression of T-cell function, including cellular expansion and activation-induced secretion of immunosuppressive mediators. Both components of MDSC bioactivity are amenable to pharmacologic intervention as discussed herein. We also focus on the relationship between MDSCs, tumor growth, therapeutic responses, and the mechanisms of cellular expansion, activation, and immunosuppression.

Original languageEnglish (US)
Pages (from-to)5243-5248
Number of pages6
JournalClinical Cancer Research
Volume13
Issue number18
DOIs
StatePublished - Sep 15 2007

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Immunosuppressive Agents
Immunosuppression
Neoplasms
T-Lymphocytes
Nitric Oxide
Myelopoiesis
Therapeutics
Reactive Nitrogen Species
Arginase
Graft vs Host Disease
Nitric Oxide Synthase Type II
Growth
Immunotherapy
Arginine
Epitopes
Reactive Oxygen Species
Intercellular Signaling Peptides and Proteins
Cell Count
Bone Marrow
Myeloid-Derived Suppressor Cells

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "Pathways mediating the expansion and immunosuppressive activity of myeloid-derived suppressor cells and their relevance to cancer therapy",
abstract = "Cancer immunotherapy has focused on inducing and expanding CTLs and improving the immune recognition of weak antigenic determinants expressed by tumors. However, few positive clinical outcomes have been reported due, in part, to tumor-associated immunologic tolerance, supporting the need for an emphasis on overcoming immunosuppression. Systemic immunosuppression is associated with abnormal myelopoiesis secondary to tumor growth, myelosuppressive therapy, and growth factor administration and subsequent expansion/mobilization of bone marrow-derived immunosuppressive cells. These myeloid-derived suppressor cells (MDSC) reduce activated T-cell number and inhibit their function by multiple mechanisms, including depletion of L-arginine by arginase-1 (ARG1) production of nitric oxide, reactive oxygen species, and reactive nitrogen oxide species by inducible nitric oxide synthase. Increased numbers of MDSCs are associated with neoplastic, inflammatory, infectious, and graft-versus-host diseases where they restrain exuberant or novel T-cell responses. In this review, we discuss critical components of MDSC-mediated suppression of T-cell function, including cellular expansion and activation-induced secretion of immunosuppressive mediators. Both components of MDSC bioactivity are amenable to pharmacologic intervention as discussed herein. We also focus on the relationship between MDSCs, tumor growth, therapeutic responses, and the mechanisms of cellular expansion, activation, and immunosuppression.",
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AB - Cancer immunotherapy has focused on inducing and expanding CTLs and improving the immune recognition of weak antigenic determinants expressed by tumors. However, few positive clinical outcomes have been reported due, in part, to tumor-associated immunologic tolerance, supporting the need for an emphasis on overcoming immunosuppression. Systemic immunosuppression is associated with abnormal myelopoiesis secondary to tumor growth, myelosuppressive therapy, and growth factor administration and subsequent expansion/mobilization of bone marrow-derived immunosuppressive cells. These myeloid-derived suppressor cells (MDSC) reduce activated T-cell number and inhibit their function by multiple mechanisms, including depletion of L-arginine by arginase-1 (ARG1) production of nitric oxide, reactive oxygen species, and reactive nitrogen oxide species by inducible nitric oxide synthase. Increased numbers of MDSCs are associated with neoplastic, inflammatory, infectious, and graft-versus-host diseases where they restrain exuberant or novel T-cell responses. In this review, we discuss critical components of MDSC-mediated suppression of T-cell function, including cellular expansion and activation-induced secretion of immunosuppressive mediators. Both components of MDSC bioactivity are amenable to pharmacologic intervention as discussed herein. We also focus on the relationship between MDSCs, tumor growth, therapeutic responses, and the mechanisms of cellular expansion, activation, and immunosuppression.

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