A Paradoxical Role for Regulatory T Cells in the Tumor Microenvironment of Pancreatic Cancer

Thomas Brouwer, Marieke Ijsselsteijn, Jan Oosting, Dina Ruano, Manon van der Ploeg, Frederike Dijk, Bert Bonsing, Arantza Fariña, Hans Morreau, Alexander Vahrmeijer, Noel de Miranda

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is considered to be a poorly immunogenic cancer type that combines a low mutation burden with a strong immunosuppressive tumor microenvironment. Regulatory T cells (Tregs) are major drivers of immune suppression but their prognostic role, particularly in gastrointestinal malignancies, remains controversial. Lymphocytic infiltration in 122 PDAC samples was assessed by multispectral immunofluorescence with anti-Keratin, -CD3, -CD8, -FOXP3 and -CD163 antibodies. Differential infiltration by Tregs was analyzed in the context of transcriptomic profiles that were available for 65 tumors. High infiltration of CD3+CD8− (mainly CD4+) T cells and, especially, of the subset expressing FOXP3 (Tregs) was associated with improved patient survival, whilst cytotoxic CD3+CD8+ T cell infiltration did not have an impact on overall survival. Transcriptomic analysis revealed three signatures in PDAC tumors comprising of epithelial-mesenchymal transition (EMT)/stromal, metabolic, and secretory/pancreatic signature. However, none of these signatures explained differences in Treg infiltration. We show that Tregs associate with improved overall survival in PDAC patients. This effect was independent of cytotoxic T cell infiltration and the transcriptomic profiles of their respective tumors. These findings provide a new layer of complexity in the study of PDAC tumor microenvironment that must be considered when developing immunotherapeutic interventions for this disease.
Original languageEnglish
Article number3862
JournalCancers
Volume14
Issue number16
DOIs
Publication statusPublished - 1 Aug 2022

Keywords

  • pancreatic ductal adenocarcinoma (PDAC)
  • prognosis
  • regulatory T cells (Treg)
  • tumor infiltrating lymphocytes (TIL)
  • tumor microenvironment (TME)

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