Skin basal cell carcinomas assemble a pro-tumorigenic spatially organized and self-propagating Trem2+ myeloid niche

  • Nat Commun. 2023 May 10;14(1):2685. doi: 10.1038/s41467-023-37993-w.
Daniel Haensel  1  2 ,  Bence Daniel  3  4 ,  Sadhana Gaddam  1  2 ,  Cory Pan  1  2 ,  Tania Fabo  1 ,  Jeremy Bjelajac  1 ,  Anna R Jussila  1  2 ,  Fernanda Gonzalez  1  2 ,  Nancy Yanzhe Li  1  2 ,  Yun Chen  5  6 ,  JinChao Hou  5 ,  Tiffany Patel  1  2 ,  Sumaira Aasi  2 ,  Ansuman T Satpathy  3  4  7 ,  Anthony E Oro  8  9
Affiliations
  • 1. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • 3. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 4. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, 94158, USA.
  • 5. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA.
  • 6. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA.
  • 7. Parker Institute of Cancer Immunotherapy, San Francisco, CA, 94305, USA.
  • 8. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 9. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
PMID: 37164949 DOI: 10.1038/s41467-023-37993-w
Abstract

Cancer immunotherapies have revolutionized treatment but have shown limited success as single-agent therapies highlighting the need to understand the origin, assembly, and dynamics of heterogeneous tumor immune niches. Here, we use single-cell and imaging-based spatial analysis to elucidate three microenvironmental neighborhoods surrounding the heterogeneous basal cell carcinoma tumor epithelia. Within the highly proliferative neighborhood, we find that TREM2+ skin cancer-associated macrophages (SCAMs) support the proliferation of a distinct tumor epithelial population through an immunosuppression-independent manner via oncostatin-M/JAK-STAT3 signaling. SCAMs represent a unique tumor-specific TREM2+ population defined by VCAM1 surface expression that is not found in normal homeostatic skin or during wound healing. Furthermore, SCAMs actively proliferate and self-propagate through multiple serial tumor passages, indicating long-term potential. The tumor rapidly drives SCAM differentiation, with intratumoral injections sufficient to instruct naive bone marrow-derived monocytes to polarize within days. This work provides mechanistic insights into direct tumor-immune niche dynamics independent of immunosuppression, providing the basis for potential combination tumor therapies.

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