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Medulloblastoma recurrence and metastatic spread are independent of colony-stimulating factor 1 receptor signaling and macrophage survival

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Abstract

Purpose

Tumor infiltration by immunosuppressive myeloid cells or tumor-associated macrophages (TAMs) contributes to tumor progression and metastasis. In contrast to their adult counterparts, higher TAM signatures do not correlate with aggressive tumor behavior in pediatric brain tumors. While prominent TAM infiltrates exist before and after radiation, the degree to which irradiated macrophages and microglia support progression or leptomeningeal metastasis remains unclear. Patients with medulloblastoma often present with distant metastases and tumor recurrence is largely incurable, making them prime candidates for the study of novel approaches to prevent neuroaxis dissemination and recurrence.

Methods

Macrophage depletion was achieved using CSF-1 receptor inhibitors (CSF-1Ri), BLZ945 and AFS98, with or without whole brain radiation in a variety of medulloblastoma models, including patient-derived xenografts bearing Group 3 medulloblastoma and a transgenic Sonic Hedgehog (Ptch1+/−, Trp53−/−) medulloblastoma model.

Results

Effective reduction of microglia, TAM, and spinal cord macrophage with CSF-1Ri resulted in negligible effects on the rate of local and spinal recurrences or survival following radiation. Results were comparable between medulloblastoma subgroups. While notably few tumor-infiltrating lymphocytes (TILs) were detected, average numbers of CD3+ TILs and FoxP3+ Tregs did not differ between groups following treatment and tumor aggressiveness by Ki67 proliferation index was unaltered.

Conclusion

In the absence of other microenvironmental influences, medulloblastoma-educated macrophages do not operate as tumor-supportive cells or promote leptomeningeal recurrence in these models. Our data add to a growing body of literature describing a distinct immunophenotype amid the medulloblastoma microenvironment and highlight the importance of appropriate pediatric modeling prior to clinical translation.

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Availability of data and materials

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

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Acknowledgements

We thank the families who kindly donated tumor tissue to establish our repository of cell lines housed in the Brain Tumor Resource Lab (www.btrl.org). Special thanks to Peter Murray and all members of the Olson and Roussel-Sherr laboratories for technical support and mentorship.

Funding

This research was supported by the Ruth L. Kirschstein National Research Service Award (5T32CA009351; EEC) and NIH Grants, 2R01CA114567 (JMO), PO1CA96832, and Core Grant CA21765 (MFR). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. We are grateful for additional generous funding from the Seattle Run of Hope, the Pediatric Brain Tumor Research Fund Guild of Seattle Children’s Hospital, Unravel Pediatric Cancer and the American Lebanese-Syrian Associated Charities.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Department of Pediatrics, Seattle Children’s Hospital, University of Washington, Seattle, WA, USA

    Erin E. Crotty & James M. Olson

  2. Fred Hutchinson Cancer Research Center, Clinical Research Division, Seattle, WA, USA

    Erin E. Crotty, Ken Brasel, Fiona Pakiam, Emily J. Girard, Andrew J. Mhyre & James M. Olson

  3. Department of Tumor Cell Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Stephanie M. C. Smith, Yamicia D. Connor, Frederique Zindy & Martine F. Roussel

  4. Medtronic, Department of Clinical Strategy, 1775, Pyramid Place TN03, Memphis, TN, 38132, USA

    Stephanie M. C. Smith

  5. Century Therapeutics, 3675 Market St., Philadelphia, PA, 19104, USA

    Ken Brasel

  6. Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Boston, MA, 02115, USA

    Yamicia D. Connor

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Contributions

EEC, YDC, SMCS, and EG performed and analyzed experiments. KB provided technical assistance. FP performed histopathological analyses. EEC, AM, MFR and JMO conceived, designed, and supervised the study. EEC wrote the manuscript with edits and final approval from all authors.

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Correspondence to Erin E. Crotty.

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All human tissue procurement was in accordance with the ethical standards of our institution and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Crotty, E.E., Smith, S.M.C., Brasel, K. et al. Medulloblastoma recurrence and metastatic spread are independent of colony-stimulating factor 1 receptor signaling and macrophage survival. J Neurooncol 153, 225–237 (2021). https://doi.org/10.1007/s11060-021-03767-x

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