Adaptive Immune Resistance Emerges from Tumor-Initiating Stem Cells

Cell. 2019 May 16;177(5):1172-1186.e14. doi: 10.1016/j.cell.2019.03.025. Epub 2019 Apr 25.

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.

Keywords: adoptive T cell transfer therapy; immune evasion; immune-stem cell interactions; lineage tracing; single-cell RNA sequencing; squamous cell carcinoma; tumor stem cell.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • Neoplasm Proteins