Transcriptomic signatures of tumors undergoing T cell attack

Cancer Immunol Immunother. 2022 Mar;71(3):553-563. doi: 10.1007/s00262-021-03015-1. Epub 2021 Jul 17.


Background: Studying tumor cell-T cell interactions in the tumor microenvironment (TME) can elucidate tumor immune escape mechanisms and help predict responses to cancer immunotherapy.

Methods: We selected 14 pairs of highly tumor-reactive tumor-infiltrating lymphocytes (TILs) and autologous short-term cultured cell lines, covering four distinct tumor types, and co-cultured TILs and tumors at sub-lethal ratios in vitro to mimic the interactions occurring in the TME. We extracted gene signatures associated with a tumor-directed T cell attack based on transcriptomic data of tumor cells.

Results: An autologous T cell attack induced pronounced transcriptomic changes in the attacked tumor cells, partially independent of IFN-γ signaling. Transcriptomic changes were mostly independent of the tumor histological type and allowed identifying common gene expression changes, including a shared gene set of 55 transcripts influenced by T cell recognition (Tumors undergoing T cell attack, or TuTack, focused gene set). TuTack scores, calculated from tumor biopsies, predicted the clinical outcome after anti-PD-1/anti-PD-L1 therapy in multiple tumor histologies. Notably, the TuTack scores did not correlate to the tumor mutational burden, indicating that these two biomarkers measure distinct biological phenomena.

Conclusions: The TuTack scores measure the effects on tumor cells of an anti-tumor immune response and represent a comprehensive method to identify immunologically responsive tumors. Our findings suggest that TuTack may allow patient selection in immunotherapy clinical trials and warrant its application in multimodal biomarker strategies.

Keywords: Adaptive immune resistance; Anti-PD-1; Anti-PD-L1; Immunotherapy biomarkers; Patient selection; Transcriptomics.

MeSH terms

  • Biomarkers, Tumor*
  • Cell Line, Tumor
  • Coculture Techniques
  • Computational Biology / methods
  • DNA Contamination
  • Gene Expression Profiling / methods
  • Gene Expression Profiling / standards
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Immune Checkpoint Inhibitors
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / metabolism*
  • Molecular Targeted Therapy
  • Neoplasms / drug therapy
  • Neoplasms / etiology*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Organ Specificity
  • ROC Curve
  • Transcriptome*
  • Tumor Cells, Cultured
  • Tumor Microenvironment / genetics*
  • Tumor Microenvironment / immunology*


  • Biomarkers, Tumor
  • Immune Checkpoint Inhibitors