Urothelial bladder cancer may suppress perforin expression in CD8+ T cells by an ICAM-1/TGFβ2 mediated pathway.

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  • Additional Information
    • Source:
      Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: eCollection Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE
    • Publication Information:
      Original Publication: San Francisco, CA : Public Library of Science
    • Subject Terms:
      Gene Expression Regulation, Neoplastic* ; Signal Transduction*; CD8-Positive T-Lymphocytes/*metabolism ; Intercellular Adhesion Molecule-1/*metabolism ; Perforin/*metabolism ; Transforming Growth Factor beta2/*metabolism ; Urinary Bladder Neoplasms/*metabolism; Aged ; Aged, 80 and over ; Female ; Humans ; Male ; Middle Aged ; Perforin/genetics ; Urinary Bladder Neoplasms/genetics ; Urinary Bladder Neoplasms/pathology
    • Abstract:
      The immune system plays a significant role in urothelial bladder cancer (UBC) progression, with CD8+ T cells being capable to directly kill tumor cells using perforin and granzymes. However, tumors avoid immune recognition by escape mechanisms. In this study, we aim to demonstrate tumor immune escape mechanisms that suppress CD8+ T cells cytotoxicity. 42 patients diagnosed with UBC were recruited. CD8+ T cells from peripheral blood (PB), sentinel nodes (SN), and tumor were analyzed in steady state and in vitro-stimulated conditions by flow cytometry, RT-qPCR, and ELISA. Mass spectrometry (MS) was used for identification of proteins from UBC cell line culture supernatants. Perforin was surprisingly found to be low in CD8+ T cells from SN, marked by 1.8-fold decrease of PRF1 expression, with maintained expression of granzyme B. The majority of perforin-deficient CD8+ T cells are effector memory T (TEM) cells with exhausted Tc2 cell phenotype, judged by the presence of PD-1 and GATA-3. Consequently, perforin-deficient CD8+ T cells from SN are low in T-bet expression. Supernatant from muscle invasive UBC induces perforin deficiency, a mechanism identified by MS where ICAM-1 and TGFβ2 signaling were causatively validated to decrease perforin expression in vitro. Thus, we demonstrate a novel tumor escape suppressing perforin expression in CD8+ T cells mediated by ICAM-1 and TGFβ2, which can be targeted in combination for cancer immunotherapy.
      Competing Interests: The authors have declared that no competing interests exist.
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    • Accession Number:
      0 (Transforming Growth Factor beta2)
      126465-35-8 (Perforin)
      126547-89-5 (Intercellular Adhesion Molecule-1)
    • Publication Date:
      Date Created: 20180703 Date Completed: 20190101 Latest Revision: 20190101
    • Publication Date:
      20240829
    • Accession Number:
      PMC6028111
    • Accession Number:
      10.1371/journal.pone.0200079
    • Accession Number:
      29966014