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Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells

Author:
Miao, Yuxuan, Yang, Hanseul, Levorse, John, Yuan, Shaopeng, Polak, Lisa, Sribour, Megan, Singh, Bhuvanesh, Rosenblum, Michael D., Fuchs, Elaine
Source:
Cell 2019 v.177 no.5 pp. 1172-1186.e14
ISSN:
0092-8674
Subject:
T-lymphocytes, cytotoxicity, immunotherapy, ligands, models, monitoring, neoplasm cells, relapse, sequence analysis, skin neoplasms, squamous cell carcinoma, stem cells, transforming growth factor beta
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.
Agid:
6429188