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Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells
Open accessAbstract
Our bodies are equipped with powerful immune surveillance to clear cancerous cells as they emerge. How tumor-initiating stem cells (tSCs) that form and propagate cancers equip themselves to overcome this barrier remains poorly understood. To tackle this problem, we designed a skin cancer model for squamous cell carcinoma (SCC) that can be effectively challenged by adoptive cytotoxic T cell transfer (ACT)-based immunotherapy. Using single-cell RNA sequencing (RNA-seq) and lineage tracing, we found that transforming growth factor β (TGF-β)-responding tSCs are superior at resisting ACT and form the root of tumor relapse. Probing mechanism, we discovered that during malignancy, tSCs selectively acquire CD80, a surface ligand previously identified on immune cells. Moreover, upon engaging cytotoxic T lymphocyte antigen-4 (CTLA4), CD80-expressing tSCs directly dampen cytotoxic T cell activity. Conversely, upon CTLA4- or TGF-β-blocking immunotherapies or Cd80 ablation, tSCs become vulnerable, diminishing tumor relapse after ACT treatment. Our findings place tSCs at the crux of how immune checkpoint pathways are activated.
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“The latter possibility is consistent with TSKs resembling tumor-initiating stem cells better equipped to survive adoptive cytotoxic T cell therapy in a mouse model of cSCC (Miao et al., 2019).”
From Multimodal Analysis of Composition and Spatial Architecture in Human Squamous Cell Carcinoma (2020) · cites this paper as Miao et al., 2019
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Immunotherapy in pancreatic cancer: overcoming the challenges of tumor heterogeneity
Nakamura, M., He, Z., Dhulia, R., Manji, G. A., & Reya, T. (2026) · Trends Open · doi:10.1016/j.treopn.2026.04.001
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Metadata
- Authors
- Miao, Y., Yang, H., Levorse, J., Yuan, S., Polak, L., Sribour, M., Singh, B., Rosenblum, M. D., & Fuchs, E.
- Affiliations
- Howard Hughes Medical Institute (US)
- Memorial Sloan Kettering Cancer Center (US)
- University of California, San Francisco (US)
- Corresponding author
- Fuchs, Elaine
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2019-05
- Volume
- 177
- Issue
- 5
- Pages
- 1172-1186.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6525024
- OpenAlex
- W2942376604
- Cited by
- 299
- References
- 52
- Citations by year
- 2026: 29 · 2025: 35 · 2024: 43 · 2023: 51 · 2022: 36 · 2021: 49 · 2020: 41 · 2019: 15
- FWCI
- 14.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Jane Coffin Childs Memorial Fund for Medical Research
- National Institutes of Health (R01-AR050452, R- 01AR27883, C32585GG)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- adaptive immune resistance, squamous cell carcinoma, skin cancer, TGF-beta, CD80, CTLA-4, immune checkpoint, tumor recurrence, immune evasion, cancer stem cells
- MeSH terms
- Animals, Carcinoma, Squamous Cell, Humans, Immunity, Cellular, Immunologic Surveillance, Mice, Transgenic, Neoplasm Proteins, Skin Neoplasms, T-Lymphocytes, Neoplastic Stem Cells, Adoptive Transfer, Cell Line, Tumor, Mice
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