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Macrophage-tumor cell interaction promotes ATRT progression and chemoresistance

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Abstract

Atypical teratoid/rhabdoid tumors (ATRT) are known for their heterogeneity concerning pathophysiology and outcome. However, predictive factors within distinct subgroups still need to be uncovered. Using multiplex immunofluorescent staining and single-cell RNA sequencing we unraveled distinct compositions of the immunological tumor microenvironment (TME) across ATRT subgroups. CD68+ cells predominantly infiltrate ATRT-SHH and ATRT-MYC and are a negative prognostic factor for patients’ survival. Within the murine ATRT-MYC and ATRT-SHH TME, Cd68+ macrophages are core to intercellular communication with tumor cells. In ATRT-MYC distinct tumor cell phenotypes express macrophage marker genes. These cells are involved in the acquisition of chemotherapy resistance in our relapse xenograft mouse model. In conclusion, the tumor cell-macrophage interaction contributes to ATRT-MYC heterogeneity and potentially to tumor recurrence.

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Acknowledgements

We thank all members of the K.K. lab for discussions and critical reading of the manuscript. We thank Annegret Rosemann and Elisabeth Jung (Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, 48149 Münster, Germany) for FACS sorting of samples, and Prof. Dr. Cornelius Faber, Nina Nagelmann and Florian Breuer (Department of Clinical Radiology, Translational Research Imaging Center (TRIC), University Hospital Münster, 48149 Münster, Germany) for MRI scanning of mice. K.K is supported by funds from the Deutsche Krebshilfe e.V. (111784), the Deutsche Kinderkrebsstiftung (DKS 2018.06) and the Innovative Forschung Münster (I-KE121502). G.M.z.H. is supported by grants from the Deutsche Forschungsgemeinschaft (DFG, ME4050/4-1, ME4050/8-1). US is supported by the Deutsche Krebshilfe e.V (111785) and the Fördergemeinschaft Kinderkrebs-Zentrum Hamburg. MH is supported by the Deutsche Forschungsgemeinschaft (DFG, HA 3060/8-1).

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, University Children’s Hospital Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Viktoria Melcher, Monika Graf, Marta Interlandi, Natalia Moreno, Flavia W. de Faria, Su Na Kim, Dennis Kastrati, Sonja Korbanka, Amelie Alfert, Thomas K. Albert & Kornelius Kerl

  2. Institute of Medical Informatics, University of Münster, 48149, Münster, Germany

    Marta Interlandi & Martin Dugas

  3. Institute of Biostatistics and Clinical Research, University of Münster, 48149, Münster, Germany

    Joachim Gerß

  4. Department of Neurology with Institute of Translational Neurology, University Hospital Münster, 48149, Münster, Germany

    Gerd Meyer zu Hörste

  5. Gerhard-Domagk-Institute of Pathology, University of Münster, 48149, Münster, Germany

    Wolfgang Hartmann

  6. Swabian Children’s Cancer Center, University Children’s Hospital Augsburg, 86156, Augsburg, Germany

    Michael C. Frühwald

  7. EU-RHAB Registry Center, 86156, Augsburg, Germany

    Michael C. Frühwald

  8. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany

    Ulrich Schüller

  9. Research Institute Children’s Cancer Center, 20251, Hamburg, Germany

    Ulrich Schüller

  10. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, 20251, Hamburg, Germany

    Ulrich Schüller

  11. Institute of Neuropathology, University Hospital Münster, 48149, Münster, Germany

    Martin Hasselblatt

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  1. Viktoria Melcher
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Contributions

Conceptualization: V.M., M.G., M.I., T.K.A. and K.K. Methodology: V.M., M.G., N.M., S.N.K., D.K., S.K., G.M.z.H. Validation: V.M., M.G., M.I., F.W.F., J.G. and T.K.A; Formal Analysis: V.M., M.G., M.I., F.W.F., J.G. and T.K.A. Investigation: V.M., M.G., M.I., N.M., S.N.K., D.K. and S.K. Writing—Original Draft: V.M., M.G., M.I., A.A., T.K.A. and K.K. Supervision: W.H., M.D., U.S., M.C.F., M.H. and K.K. Funding Acquisition: K.K. and M.D.

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Correspondence to Kornelius Kerl.

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Viktoria Melcher, Monika Graf and Marta Interlandi: co-first authors.

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Melcher, V., Graf, M., Interlandi, M. et al. Macrophage-tumor cell interaction promotes ATRT progression and chemoresistance. Acta Neuropathol 139, 913–936 (2020). https://doi.org/10.1007/s00401-019-02116-7

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