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 journalArticle

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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.

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

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Non-Small Cell Lung Carcinoma
Immunosuppression
Neoplasm Metastasis
Ligands
Brain
Monocytes
Conditioned Culture Medium
Neoplasms
Lung Neoplasms
Interleukin-6
Myeloid Cells
Immunosuppressive Agents
Brain Neoplasms
T-Lymphocytes
Interleukin-6 Receptors
Lung
Regulatory T-Lymphocytes
Cell Survival
Flow Cytometry
Cell Culture Techniques

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

Cite this

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer. / Li, Yuping D.; Lamano, Jonathan B.; Lamano, Jason B.; Quaggin-Smith, Jessica; Veliceasa, Dorina; Kaur, Gurvinder; Biyashev, Dauren; Unruh, Dusten; Bloch, Orin.

In: Cancer Immunology, Immunotherapy, Vol. 68, No. 9, 01.09.2019, p. 1501-1513.

Research output: Contribution to journalArticle

Li, YD, Lamano, JB, Lamano, JB, Quaggin-Smith, J, Veliceasa, D, Kaur, G, Biyashev, D, Unruh, D & Bloch, O 2019, 'Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer', Cancer Immunology, Immunotherapy, vol. 68, no. 9, pp. 1501-1513. https://doi.org/10.1007/s00262-019-02384-y
Li, Yuping D. ; Lamano, Jonathan B. ; Lamano, Jason B. ; Quaggin-Smith, Jessica ; Veliceasa, Dorina ; Kaur, Gurvinder ; Biyashev, Dauren ; Unruh, Dusten ; Bloch, Orin. / Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer. In: Cancer Immunology, Immunotherapy. 2019 ; Vol. 68, No. 9. pp. 1501-1513.
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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. Na{\"i}ve 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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T1 - Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer

AU - Li, Yuping D.

AU - Lamano, Jonathan B.

AU - Lamano, Jason B.

AU - Quaggin-Smith, Jessica

AU - Veliceasa, Dorina

AU - Kaur, Gurvinder

AU - Biyashev, Dauren

AU - Unruh, Dusten

AU - Bloch, Orin

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N2 - 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.

AB - 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.

KW - Brain metastasis

KW - IL-6

KW - Immune checkpoint

KW - Interleukin 6

KW - Non-small cell lung cancer

KW - PD-L1

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