Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells.

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.

• Authors: Yuxuan Miao, Hanseul Yang, John Levorse, Shaopeng Yuan, Lisa Polak, Megan Sribour, Bhuvanesh Singh, Michael D Rosenblum, Elaine Fuchs
• Journal: Cell (Cell) Vol. 177 Issue 5 Pg. 1172-1186.e14 (05 16 2019) ISSN: 1097-4172 [Electronic] United States
• PMID: 31031009 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Neoplasm Proteins

Topics

• Adoptive Transfer
• Animals
• Carcinoma, Squamous Cell (immunology, pathology, therapy)
• Cell Line, Tumor
• Humans
• Immunity, Cellular
• Immunologic Surveillance
• Mice
• Mice, Transgenic
• Neoplasm Proteins (immunology)
• Neoplastic Stem Cells (immunology, pathology)
• Skin Neoplasms (immunology, pathology, therapy)
• T-Lymphocytes (immunology, pathology)