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Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells

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