Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells.
Cell
; 177(5): 1172-1186.e14, 2019 05 16.
Article
in En
| MEDLINE
| ID: mdl-31031009
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 ß (TGF-ß)-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-ß-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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Skin Neoplasms
/
Neoplastic Stem Cells
/
Carcinoma, Squamous Cell
/
T-Lymphocytes
/
Adoptive Transfer
/
Immunity, Cellular
/
Immunologic Surveillance
Type of study:
Prognostic_studies
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2019
Type:
Article
Affiliation country:
United States