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

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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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Abbreviations

BM:

Brain metastasis

BMCM:

Brain metastasis conditioned media

CTLA-4:

Cytotoxic T lymphocyte antigen 4

ECOG:

Eastern Cooperative Oncology Group

FDA:

Food and Drug Administration

FFPE:

Formalin-fixed, paraffin-embedded

FMO:

Fluorescence minus one

HPFs:

High powered fields

MDSC:

Myeloid-derived suppressor cells

NCI:

National Cancer Institute

NINDS:

National Institute of Neurological Disorders and Stroke

NSCLC:

Non-small cell lung cancer

PBL:

Peripheral blood leukocytes

PBMC:

Peripheral blood mononuclear cells

PD-1:

Programmed death 1

PD-L1:

Programmed death-ligand 1

PFS:

Progression-free survival

PMA:

Propidium monoazide

RECIST:

Response evaluation criteria in solid tumors

SIL:

Siltuximab, anti-IL6 antibody

TCGA:

The Cancer Genome Atlas

TCZ:

Tocilizumab, anti-IL6-receptor antibody

Treg:

Regulatory T cell

TTF-1:

Thyroid transcription factor 1

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Acknowledgements

The authors would like to thank the Nervous System Tumor Bank at Northwestern University, without which the current study would not be possible. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by NCI CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center.

Funding

This work was supported by the Howard Hughes Medical Institute Medical Student Research Fellows program (Yuping D. Li) as well as by the NIH/National Cancer Institute (NCI) Ruth L. Kirschtein National Research Service Award F30 (CA206413; Jonathan B Lamano), NIH/NCI R01 (CA164714; Orin Bloch), and NIH/National Institute of Neurological Disorders and Stroke (NINDS) R00 (NS078055; Orin Bloch).

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Authors and Affiliations

  1. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Yuping D. Li, Jonathan B. Lamano, Jessica Quaggin-Smith, Dorina Veliceasa, Gurvinder Kaur, Dauren Biyashev & Dusten Unruh

  2. Stritch School of Medicine, Loyola University Chicago, Maywood, IL, USA

    Jason B. Lamano

  3. Department of Neurological Surgery, University of California – Davis, 4860 Y Street, Suite 3740, Sacramento, CA, 95817, USA

    Orin Bloch

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Contributions

YDL took part in conceptualization, experimental design, data curation, formal analysis, funding acquisition, methodology, validation, and writing the manuscript. JBL took part in conceptualization, experimental design, data curation and formal analysis. JBL took part in data curation, formal analysis, methodology, and validation. JQ-S and DV took part in experimental design and data curation. GK, and DB took part in data curation. DU took part in formal analysis. OB took part in conceptualization, funding acquisition, investigation, methodology, and supervision. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Orin Bloch.

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The authors declare that they have no conflicts of interest.

Ethical approval and ethical standards

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board of Northwestern University, Feinberg School of Medicine (STU00204920).

Informed consent

Written informed consent was obtained from all individual participants included in the study for the use of their blood and tumor specimen for research. Consent was not required for collection of patient characteristics as information was de-identified. Consent was not required for TCGA data collection as the TCGA is a de-identified, public database.

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This work was previously published as an abstract at the 2018 American Association of Neurological Surgeons (AANS) Annual Scientific Meeting in New Orleans, LA, USA on April 29-May 2, 2018 [1].

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Li, Y.D., Lamano, J.B., Lamano, J.B. et al. Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer. Cancer Immunol Immunother 68, 1501–1513 (2019). https://doi.org/10.1007/s00262-019-02384-y

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