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Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy

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Abstract

Immune function relies on an appropriate balance of the lymphoid and myeloid responses. In the case of neoplasia, this balance is readily perturbed by the dramatic expansion of immature or dysfunctional myeloid cells accompanied by a reciprocal decline in the quantity/quality of the lymphoid response. In this review, we seek to: (1) define the nature of the atypical myelopoiesis observed in cancer patients and the impact of this perturbation on clinical outcomes; (2) examine the potential mechanisms underlying these clinical manifestations; and (3) explore potential strategies to restore normal myeloid cell differentiation to improve activation of the host antitumor immune response. We posit that fundamental alterations in myeloid homeostasis triggered by the neoplastic process represent critical checkpoints that govern therapeutic efficacy, as well as offer novel cellular-based biomarkers for tracking changes in disease status or relapse.

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Abbreviations

AML:

Acute myeloid leukemia

APC:

Antigen-presenting cell

ATRA:

All-trans retinoic acid

CD:

Cluster of differentiation

C/EBPα:

CCAAT/enhancer binding protein α

CML:

Chronic myeloid leukemia

CMP:

Common myeloid progenitors

COX:

Cyclooxygenase

CTLA-4:

Cytotoxic T lymphocyte-associated protein 4

DC:

Dendritic cell

GATA-3:

GATA-binding protein 3

G-CSF:

Granulocyte colony-stimulating factor

GMP:

Granulocyte–monocyte progenitors

GM-CSF:

Granulocyte–macrophage colony-stimulating factor

HLA-DR:

Human leukocyte antigen-DR

HSC:

Hematopoietic stem cell

IDO:

Indoleamine 2,3-dioxygenase

IFN:

Interferon

IL:

Interleukin

iNOS:

Inducible nitric oxide synthase

IRF-8:

Interferon regulatory factor 8

MDSC:

Myeloid-derived suppressor cells

MHC:

Major histocompatibility complex

MMP:

Matrix metalloproteinase

MPP:

Multi-potent progenitor

PAX5:

Paired box protein Pax-5

PDE:

Phosphodiesterase

PD-L1:

Programmed death-ligand 1

PPARγ:

Peroxisome proliferator-activated receptor γ

PU.1:

PU box binding transcription factor PU.1

RANTES:

Regulated on activation, normal T cell expressed and secreted

RORγt:

RAR-related orphan receptor γ t

STAT:

Signal transducer and activator of transcription

TAM:

Tumor-associated macrophage

TAN:

Tumor-associated neutrophil

TAP:

Transporter associated with antigen processing

T-bet:

T box transcription factor

TDF:

Tumor-derived factor

TGF-β:

Transforming growth factor-β

Th :

T helper subset

TLRs:

Toll-like receptors

TNFα:

Tumor necrosis factor α

Tregs :

T regulatory cells

VEGF:

Vascular endothelial growth factor

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Acknowledgments

This work was supported by National Institute of Health Grant R01CA140622 (to Scott I. Abrams), an Alliance Development Award from the Roswell Park Alliance Foundation (to Scott I. Abrams), Department of Defense Award W81XWH-11-1-0394 (to Scott I. Abrams) and National Institute of Health Training Grant T32CA085183 (to Colleen S. Netherby).

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  1. Department of Immunology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY, 14263, USA

    Michelle N. Messmer, Colleen S. Netherby, Debarati Banik & Scott I. Abrams

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  1. Michelle N. Messmer
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  2. Colleen S. Netherby
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Correspondence to Scott I. Abrams.

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Messmer, M.N., Netherby, C.S., Banik, D. et al. Tumor-induced myeloid dysfunction and its implications for cancer immunotherapy. Cancer Immunol Immunother 64, 1–13 (2015). https://doi.org/10.1007/s00262-014-1639-3

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