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@ARTICLE{Heiduk:277756,
      author       = {M. Heiduk and A. Klimova and C. Reiche and D. Digomann and
                      C. Beer and D. E. Aust and M. Distler and J. Weitz$^*$ and
                      A. M. Seifert$^*$ and L. Seifert$^*$},
      title        = {{TIGIT} {E}xpression {D}elineates {T}-cell {P}opulations
                      with {D}istinct {F}unctional and {P}rognostic {I}mpact in
                      {P}ancreatic {C}ancer.},
      journal      = {Clinical cancer research},
      volume       = {29},
      number       = {14},
      issn         = {1078-0432},
      address      = {Philadelphia, Pa. [u.a.]},
      publisher    = {AACR},
      reportid     = {DKFZ-2023-01473},
      pages        = {2638 - 2650},
      year         = {2023},
      abstract     = {Immunotherapy has led to a fundamental shift in the
                      treatment of several cancers. However, its efficacy in
                      pancreatic ductal adenocarcinoma (PDAC) is limited.
                      Understanding the expression of inhibitory immune checkpoint
                      receptors (ICR) by intratumoral T cells may help to unravel
                      their involvement in insufficient T-cell-mediated antitumor
                      immunity.Using multicolor flow cytometry, we analyzed
                      circulating and intratumoral T cells from blood (n = 144)
                      and matched tumor samples (n = 107) of patients with PDAC.
                      We determined the expression of programmed cell death
                      protein 1 (PD-1) and T-cell immunoreceptor with Ig and
                      immunoreceptor tyrosine-based inhibition motif (ITIM)
                      domains (TIGIT) by CD8+ T-cells, conventional CD4+ T-cells
                      (Tconv) and regulatory T cells (Treg) and their association
                      with T-cell differentiation, tumor reactivity, and cytokine
                      expression. A comprehensive follow-up was used to determine
                      their prognostic value.Intratumoral T cells were
                      characterized by increased PD-1 and TIGIT expression. Both
                      markers delineated distinct T-cell subpopulations.
                      PD-1+TIGIT- T cells highly expressed proinflammatory
                      cytokines and markers of tumor reactivity (CD39, CD103),
                      whereas TIGIT expression was linked to antiinflammatory and
                      exhausted phenotypes. In addition, the enhanced presence of
                      intratumoral PD-1+TIGIT- Tconv was associated with improved
                      clinical outcomes, while high ICR expression on blood T
                      cells was a significant hazard for overall survival (OS).Our
                      results uncover the association between ICR expression and
                      T-cell functionality. PD-1 and TIGIT characterized
                      intratumoral T cells with highly divergent phenotypes linked
                      to clinical outcomes, further underscoring the relevance of
                      TIGIT for immunotherapeutic approaches in PDAC. The
                      prognostic value of ICR expression in patient blood may be a
                      valuable tool for patient stratification.},
      keywords     = {Humans / Programmed Cell Death 1 Receptor: metabolism /
                      Prognosis / CD8-Positive T-Lymphocytes / Receptors,
                      Immunologic: genetics / Pancreatic Neoplasms: metabolism /
                      Programmed Cell Death 1 Receptor (NLM Chemicals) /
                      Receptors, Immunologic (NLM Chemicals) / TIGIT protein,
                      human (NLM Chemicals)},
      cin          = {DD01},
      ddc          = {610},
      cid          = {I:(DE-He78)DD01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37140899},
      pmc          = {pmc:PMC10345964},
      doi          = {10.1158/1078-0432.CCR-23-0258},
      url          = {https://inrepo02.dkfz.de/record/277756},
}