Myeloid-targeting immunotherapies overcome inhibitory barriers in immune-evasive neuroblastoma
Neuroblastomas are highly heterogeneous tumors originating from neural crest-derived cells destined to form the sympathetic nervous system. Nearly half of high-risk tumors present with amplification of the MYCN proto-oncogene. Here, we describe a Mycn-driven, transplantable, non-germline, genetically engineered mouse model (Mycn-nGEMM). Mycn-nGEMM tumors recapitulate the immune-evasive, macrophage-rich tumor microenvironment of high-risk, MYCN-amplified human neuroblastoma. Treatment of tumor-bearing mice with anti-PD-L1, but not anti-PD-1 or anti-CTLA-4, inhibited tumor growth, profoundly remodeling the tumor microenvironment by depleting anti-inflammatory macrophages and increasing T cell infiltration. Surprisingly, while tumor cells showed low expression of PD-L1, anti-inflammatory macrophages from both murine and human neuroblastoma expressed PD-L1. We identified cytokines, including macrophage migration inhibitory factor, secreted by the Mycn-nGEMM cancer cells that drive expression of PD-L1 on macrophages. Combining anti-PD-L1 with CD40 agonist antibodies further improved survival in Mycn-nGEMM mice, demonstrating the potential for myeloid-targeting immunotherapies to overcome inhibitory barriers in immune-evasive neuroblastoma.
Authors
- John M. Maris (ORCID: https://orcid.org/0000-0002-8088-7929)
- Marie Ménard (ORCID: https://orcid.org/0000-0003-1511-4361)
- Hiroyuki Shimada (ORCID: https://orcid.org/0000-0001-5025-7507)
- G. Esteban Fernández (ORCID: https://orcid.org/0000-0002-8393-9229)
- Nicole Nasholm (ORCID: https://orcid.org/0000-0002-5451-4985)
- L. Wang
- Hiroyuki Yoda (ORCID: https://orcid.org/0000-0002-5528-8940)
- Rebecca Kaufman (ORCID: https://orcid.org/0000-0001-8535-9730)
- Rebekah Kennedy (ORCID: https://orcid.org/0000-0002-5613-4230)
- Lee McHenry
- Edbert D Lu (ORCID: https://orcid.org/0000-0003-1411-6584)
- Liron D. Grossmann (ORCID: https://orcid.org/0000-0002-0692-8921)
- Vanessa Lopez (ORCID: https://orcid.org/0000-0002-8340-5411)
- William A. Weiss (ORCID: https://orcid.org/0000-0003-2230-9132)
- Shannon Wong‐Michalak (ORCID: https://orcid.org/0000-0002-6932-6039)
- Erin F. Simonds (ORCID: https://orcid.org/0000-0002-3497-4861)
- W. Clay Gustafson (ORCID: https://orcid.org/0000-0002-1812-5675)
- Shahab Asgharzadeh (ORCID: https://orcid.org/0000-0002-0510-3848)
- Megumi J. Barata
- A. Farrel (ORCID: https://orcid.org/0000-0003-1942-5992)
Institutions
- Twitter (United States) (US)
- University of Southern California (US)
- Children's Hospital of Philadelphia (US)
- Children's Hospital of Los Angeles (US)
- University of California, San Francisco (US)
- Sheba Medical Center (IL)
- Stanford Medicine (US)
- Neurological Surgery (US)
- UCSF Helen Diller Family Comprehensive Cancer Center (US)
- University of Pennsylvania (US)
- Stanford University (US)
Publication Details
- Journal
- The Journal of Experimental Medicine
- Published
- 2025-07-14
- DOI
- https://doi.org/10.1084/jem.20231417
- Citations
- 1
- Primary Topic
- Neuroblastoma Research and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.39
Funders
- U.S. Department of Defense
- Alex's Lemonade Stand Foundation for Childhood Cancer
- St. Baldrick's Foundation
- Uehara Memorial Foundation
- National Cancer Center
- Cancer Research UK
- National Institutes of Health