Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis

Andrea Schietinger, Mary Philip, Varintra E. Krisnawan, Edison Y. Chiu, Jeffrey J. Delrow, Ryan S. Basom, Peter Lauer, Dirk G. Brockstedt, Sue E. Knoblaugh, Günter J. Hämmerling, Todd D. Schell, Natalio Garbi, Philip D. Greenberg

Research output: Contribution to journalArticlepeer-review

459 Scopus citations


CD8+ T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8+ T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)389-401
Number of pages13
Issue number2
StatePublished - 2016

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases


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