Mechanisms of T-Cell Exhaustion in Pancreatic Cancer.

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Saka D., Gokalp M., Piyade B., Cevik N. C., Sever E., Unutmaz D., ...More

Cancers, vol.12, no.8, 2020 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 12 Issue: 8
  • Publication Date: 2020
  • Doi Number: 10.3390/cancers12082274
  • Journal Name: Cancers
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, BIOSIS, CAB Abstracts, CINAHL, EMBASE, Veterinary Science Database, Directory of Open Access Journals
  • Keywords: pancreatic ductal adenocarcinoma, PDAC, T-cell exhaustion, epigenetics, Thymocyte selection-associated high mobility group box protein, TOXs, tumor microenvironment, TME, ENDOTHELIAL GROWTH-FACTOR, TUMOR-INFILTRATING MACROPHAGES, SUPPRESSOR-CELLS, DUCTAL ADENOCARCINOMA, ARGININE DEPRIVATION, TH17 CELLS, PROGNOSTIC-SIGNIFICANCE, TRANSCRIPTION FACTOR, LYMPHOCYTES REVEALS, PERIPHERAL-BLOOD
  • Acibadem Mehmet Ali Aydinlar University Affiliated: Yes


T-cell exhaustion is a phenomenon that represents the dysfunctional state of T cells in chronic infections and cancer and is closely associated with poor prognosis in many cancers. The endogenous T-cell immunity and genetically edited cell therapies (CAR-T) failed to prevent tumor immune evasion. The effector T-cell activity is perturbed by an imbalance between inhibitory and stimulatory signals causing a reprogramming in metabolism and the high levels of multiple inhibitory receptors like programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3), and Lymphocyte-activation gene 3 (Lag-3). Despite the efforts to neutralize inhibitory receptors by a single agent or combinatorial immune checkpoint inhibitors to boost effector function, PDAC remains unresponsive to these therapies, suggesting that multiple molecular mechanisms play a role in stimulating the exhaustion state of tumor-infiltrating T cells. Recent studies utilizing transcriptomics, mass cytometry, and epigenomics revealed a critical role of Thymocyte selection-associated high mobility group box protein (TOX) genes and TOX-associated pathways, driving T-cell exhaustion in chronic infection and cancer. Here, we will review recently defined molecular, genetic, and cellular factors that drive T-cell exhaustion in PDAC. We will also discuss the effects of available immune checkpoint inhibitors and the latest clinical trials targeting various molecular factors mediating T-cell exhaustion in PDAC.