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Increased CD14+HLA-DR-/low myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients

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Abstract

Accumulating evidence has demonstrated that myeloid-derived suppressor cells (MDSCs), a heterogeneous population of cells, play an important role in the subversion, inhibition, and downregulation of the immune response to cancer. However, the characteristics of these cells, particularly clinical relevance, in malignant tumors remain unclear due to a lack of specific markers. In this study, we characterized peripheral CD14+HLA-DR-/low cells, a new human MDSC subpopulation, in 89 patients with non-small cell lung cancer (NSCLC). As expected, both frequency and absolute number of CD14+HLA-DR-/low cells were significantly increased in the peripheral blood of NSCLC patients compared with that of the healthy controls and indicated an association with metastasis, response to chemotherapy, and progression-free survival. These cells showed decreased expression of CD16 and CD86 compared with HLA-DR+ monocytes. Unlike classical monocytes, these populations showed significantly decreased allostimulatory activity and showed the ability to inhibit autologous T cell proliferation and IFN-γ production in a cell-contact-dependent manner. Furthermore, we demonstrated that CD14+HLA-DR-/low cells expressed the NADPH oxidase component gp91phox and generated high level of reactive oxygen species (ROS). Moreover, inactivation of ROS reversed their immunosuppressive capacity on T cell response. These results prove, for the first time, the existence of ROS-producing CD14+HLA-DR-/low myeloid-derived suppressor cells in NSCLC patients, which mediate tumor immunosuppression and might thus represent a potential target for therapeutic intervention.

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Abbreviations

MDSCs:

Myeloid-derived suppressor cells

AS:

Adenocarcinoma

SCC:

Squamous cell carcinoma

RECIST:

Response Evaluation Criteria in Solid Tumors

PFS:

Progression-free survival

L-NMMA:

NG-Methyl-l-arginine acetate salt

nor-NOHA:

Nω-Hydroxy-nor-l-arginine, diacetate salt

CD14depl :

CD14-depleted

Arg1:

Arginase-1

iNOS:

Inducible nitric oxide synthase

Cox2:

Cyclooxygenase 2

IDO:

Indoleamine 2, 3-dioxygenase

NADPH:

Nicotinamide adenine dinucleotide phosphate

DCF:

2′,7′-dichlorofluorescein

ROS:

Reactive oxygen species

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Acknowledgments

This study was supported by grants from the Ministry of Science and Technology of China (“973” projects) (No. 2012CB917104) and the National Natural Science Foundation of China (No. 81172853 and No. 81201605).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Cancer Center, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China

    Ang Huang, Bo Wang, Fan Zhang, Ke-Xing Fan & Ya-Jun Guo

  2. International Joint Cancer Institute, The Second Military Medical University, 800 Xiang Yin Road, New Building West 10-11th Floor, Shanghai, 200433, People’s Republic of China

    Bo Zhang, Ke-Xing Fan & Ya-Jun Guo

  3. Department of Infectious Diseases, Beijing 302 Hospital, Beijing, 100039, People’s Republic of China

    Ang Huang

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  1. Ang Huang
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Correspondence to Ke-Xing Fan or Ya-Jun Guo.

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Ang Huang and Bo Zhang contributed equally to this work as first authors.

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Huang, A., Zhang, B., Wang, B. et al. Increased CD14+HLA-DR-/low myeloid-derived suppressor cells correlate with extrathoracic metastasis and poor response to chemotherapy in non-small cell lung cancer patients. Cancer Immunol Immunother 62, 1439–1451 (2013). https://doi.org/10.1007/s00262-013-1450-6

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