Cited by 303Cancer Immunotherapy and BiomarkersCancer Cells and MetastasisImmunotherapy and Immune Responses

Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells

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Miao, Yuxuan, Yang, Hanseul, Levorse, John, Yuan, Shaopeng, Polak, Lisa, Sribour, Megan, Singh, Bhuvanesh, Rosenblum, Michael D. +1 more·2019·Cell

Abstract

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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Crossref · 10.1016/j.cell.2019.03.025

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  • TSKs resemble tumor-initiating stem cells better equipped to survive adoptive cytotoxic T cell therapy in a mouse model of cSCC.

    “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).”

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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
Venue
Cell
Publisher
Elsevier BV
Published
2019-05
Volume
177
Issue
5
Pages
1172-1186.e14
ISSN
0092-8674 (ISSN-L)
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
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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