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

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

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1501-1513
Number of pages13
JournalCancer Immunology, Immunotherapy
Volume68
Issue number9
DOIs
StatePublished - Sep 1 2019

Keywords

  • Brain metastasis
  • IL-6
  • Immune checkpoint
  • Interleukin 6
  • Non-small cell lung cancer
  • PD-L1

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

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