XAF1 is secreted from stressed tumor cells to activate T cell-mediated tumor surveillance via Lck-ERK signaling.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: United States NLM ID: 100886622 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5586 (Electronic) Linking ISSN: 14765586 NLM ISO Abbreviation: Neoplasia Subsets: MEDLINE
    • Publication Information:
      Publication: 2014- : [Amsterdam] : Elsevier
      Original Publication: New York, NY : Stockton Press, c1999-
    • Subject Terms:
      T-Lymphocytes*/metabolism ; T-Lymphocytes*/immunology ; Adaptor Proteins, Signal Transducing*/metabolism ; Adaptor Proteins, Signal Transducing*/genetics ; Intracellular Signaling Peptides and Proteins*/metabolism ; Intracellular Signaling Peptides and Proteins*/genetics; Humans ; Animals ; Mice ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/metabolism ; Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/genetics ; MAP Kinase Signaling System ; Cell Line, Tumor ; Neoplasms/metabolism ; Neoplasms/pathology ; Neoplasms/genetics ; Neoplasms/immunology ; Neoplasms/etiology ; Signal Transduction ; Immunologic Surveillance ; Apoptosis Regulatory Proteins
    • Abstract:
      X-linked inhibitor of apoptosis-associated factor 1 (XAF1) is a stress-inducible tumor suppressor that is commonly inactivated in multiple types of human malignancies. Nevertheless, the molecular basis for the XAF1-mediated tumor suppression remains largely undefined. Here, we report that XAF1 is secreted from cells under various cytotoxic stress conditions and activates T cell-mediated tumor surveillance. In cancer cells exposed to interferon -γ, tumor necrosis factor -α, and etoposide, XAF1 is elevated and actively secreted through the unconventional endo-lysosomal trafficking pathway and the zinc finger 4 domain of XAF1 plays an essential for this secretion. Secreted XAF1 is internalized into nearby T cells through clathrin-mediated endocytosis and stimulates proliferation, migration, and tumor infiltration of T cells. Internalized XAF1 activates RAF-MEK-ERK signaling through the direct interaction with and phosphorylation of lymphocyte-specific protein tyrosine kinase. In response to interferon -γ injection, Xaf1 + /+ tumors display significantly higher regression rate and T cell infiltration compared to Xaf1 -/- tumors while Xaf1 -/- tumors are markedly reduced by injection of recombinant Xaf1. XAF1 expression is associated with overall survival in T cell-enriched cancer patients and also correlates with prognosis in T cell-based immunotherapies. Together, our study identifies XAF1 as a novel secretory immune-modulatory tumor suppressor, illuminating the mechanistic consequence of its inactivation in tumorigenesis.
      Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest.
      (Copyright © 2024. Published by Elsevier Inc.)
    • Contributed Indexing:
      Keywords: Lck; Secretion; T cells; Tumor microenvironment; XAF1
    • Accession Number:
      0 (Adaptor Proteins, Signal Transducing)
      0 (Intracellular Signaling Peptides and Proteins)
      EC 2.7.10.2 (Lymphocyte Specific Protein Tyrosine Kinase p56(lck))
      0 (XAF1 protein, human)
      0 (Apoptosis Regulatory Proteins)
    • Publication Date:
      Date Created: 20241130 Date Completed: 20241218 Latest Revision: 20241218
    • Publication Date:
      20241219
    • Accession Number:
      10.1016/j.neo.2024.101094
    • Accession Number:
      39615106