Superparamagnetic Iron Oxide Nanoparticles Reprogram the Tumor Microenvironment and Reduce Lung Cancer Regrowth after Crizotinib Treatment

ACS Nano, vol. 18, pp. 11025–11041

Abstract

High Resolution Image Download MS PowerPoint Slide ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8 + T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors.

Authors 16

1. Natalie K. Horvat

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

   Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

   Ruprecht Karl University of Heidelberg, 69120, Heidelberg, Germany

2. Sara Chocarro

   German Cancer Research Center · Heidelberg University

   Affiliation as printed

   Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

   Ruprecht Karl University of Heidelberg, 69120, Heidelberg, Germany

3. Oriana Marques

   Heidelberg University · University Hospital Heidelberg

   Affiliation as printed

   Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

   Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

4. Tobias Alexander Bauer Aachen Leiden Academic Centre for Drug Research

   Leiden University

   Affiliation as printed

   Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands

5. Ruiyue Qiu

   University Hospital Heidelberg

   Affiliation as printed

   Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

6. Alberto Diaz-Jimenez

   German Cancer Research Center · Heidelberg University

   Affiliation as printed

   Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

   Ruprecht Karl University of Heidelberg, 69120, Heidelberg, Germany

7. Barbara Helm

   German Cancer Research Center · German Center for Lung Research

   Affiliation as printed

   Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

   German Center for Lung Research (DZL) and Translational Lung Research Center Heidelberg (TRLC), 69120, Heidelberg, Germany

8. Yuanyuan Chen

   German Cancer Research Center

   Affiliation as printed

   Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

9. Stefan Sawall

   German Cancer Research Center

   Affiliation as printed

   X-ray Imaging and CT, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

10. Richard Sparla

    University Hospital Heidelberg

    Affiliation as printed

    Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

11. Lu Su Aachen Leiden Academic Centre for Drug Research

    Leiden University

    Affiliation as printed

    Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands

12. Ursula Klingmüller

    German Cancer Research Center · German Center for Lung Research · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    German Center for Lung Research (DZL) and Translational Lung Research Center Heidelberg (TRLC), 69120, Heidelberg, Germany

    German Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany

13. Matthias Barz Aachen Leiden Academic Centre for Drug Research

    Leiden University · University Medical Center of the Johannes Gutenberg University Mainz

    Affiliation as printed

    Department of Dermatology, University Medical Center of the Johannes Gutenberg University Mainz, Langenbeckstraße 1, 55131, Mainz, Germany

    Leiden Academic Centre for Drug Research (LACDR), Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands

14. Matthias W. Hentze corresponding

    Heidelberg University · European Molecular Biology Laboratory · European Molecular Biology Laboratory

    Affiliation as printed

    European Molecular Biology Laboratory (EMBL), Meyerhofstr.1, 69117, Heidelberg, Germany

    Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

15. Rocı́o Sotillo corresponding

    German Cancer Research Center · German Center for Lung Research · Deutsches Konsortium für Translationale Krebsforschung

    Affiliation as printed

    Division of Molecular Thoracic Oncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    German Center for Lung Research (DZL) and Translational Lung Research Center Heidelberg (TRLC), 69120, Heidelberg, Germany

    German Consortium for Translational Cancer Research (DKTK), 69120, Heidelberg, Germany

16. Martina Ulrike Muckenthaler corresponding

    Heidelberg University · University Hospital Heidelberg · German Centre for Cardiovascular Research · German Center for Lung Research

    Affiliation as printed

    Department of Pediatric Hematology, Oncology, Immunology and Pulmonology, Heidelberg University Hospital, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany

    German Center for Lung Research (DZL) and Translational Lung Research Center Heidelberg (TRLC), 69120, Heidelberg, Germany

    German Centre for Cardiovascular Research (DZHK), Partner Site, 69120, Heidelberg/Mannheim, Germany

    Molecular Medicine Partnership Unit (MMPU), Otto-Meyerhof-Zentrum, Im Neuenheimer Feld 350, 69120, Heidelberg, Germany