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Published in: Cancer Immunology, Immunotherapy 9/2019

01-09-2019 | NSCLC | Original Article

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer

Authors: Yuping D. Li, Jonathan B. Lamano, Jason B. Lamano, Jessica Quaggin-Smith, Dorina Veliceasa, Gurvinder Kaur, Dauren Biyashev, Dusten Unruh, Orin Bloch

Published in: Cancer Immunology, Immunotherapy | Issue 9/2019

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Abstract

Introduction

Brain metastases are a significant source of morbidity and mortality for patients with lung cancer. Lung cancer can induce local and systemic immunosuppression, promoting tumor growth and dissemination. One mechanism of immunosuppression is tumor-induced expansion of programmed death-ligand 1 (PD-L1) expressing myeloid cells. Here, we investigate peripheral blood immune phenotype in NSCLC patients with or without brain metastasis.

Methods

Peripheral blood was collected from patients with lung metastatic brain tumors and pre-metastatic lung cancer. Immunosuppressive monocytes, myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs) were quantified through flow cytometry. T cell reactivity was analyzed via ELISpot. Brain metastasis conditioned media was collected from tumor-derived cell cultures and analyzed for cytokines by ELISA. Naïve monocytes were stimulated with brain metastasis conditioned media to evaluate PD-L1 stimulation.

Results

Patients with brain metastatic lung carcinoma demonstrated increased peripheral monocyte PD-L1, MDSC abundance, and Treg percentage compared to early stage pre-metastatic patients and healthy controls. Patients with elevated peripheral monocyte PD-L1 had less reactive T cells and worse survival. Brain metastasis conditioned media stimulation increased monocyte PD-L1, and conditioned media IL-6 levels correlated with PD-L1 induction. Treatment with anti-IL-6 or anti-IL-6 receptor antibodies reduced PD-L1 expression. In summary, patients with lung cancer and brain metastases exhibit multiple markers of peripheral immunosuppression.

Conclusions

The frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases. Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients.
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Metadata
Title
Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer
Authors
Yuping D. Li
Jonathan B. Lamano
Jason B. Lamano
Jessica Quaggin-Smith
Dorina Veliceasa
Gurvinder Kaur
Dauren Biyashev
Dusten Unruh
Orin Bloch
Publication date
01-09-2019
Publisher
Springer Berlin Heidelberg
Published in
Cancer Immunology, Immunotherapy / Issue 9/2019
Print ISSN: 0340-7004
Electronic ISSN: 1432-0851
DOI
https://doi.org/10.1007/s00262-019-02384-y

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