Frontiers in Immunology (Oct 2024)

HLA-G expression associates with immune evasion muscle-invasive urothelial cancer and drives prognostic relevance

  • Annalena Branz,
  • Annalena Branz,
  • Annalena Branz,
  • Annalena Branz,
  • Christian Matek,
  • Christian Matek,
  • Christian Matek,
  • Christian Matek,
  • Fabienne Lange,
  • Fabienne Lange,
  • Fabienne Lange,
  • Fabienne Lange,
  • Veronika Bahlinger,
  • Veronika Bahlinger,
  • Veronika Bahlinger,
  • Veronika Bahlinger,
  • Veronika Bahlinger,
  • Niklas Klümper,
  • Niklas Klümper,
  • Niklas Klümper,
  • Michael Hölzel,
  • Michael Hölzel,
  • Pamela L. Strissel,
  • Pamela L. Strissel,
  • Pamela L. Strissel,
  • Pamela L. Strissel,
  • Pamela L. Strissel,
  • Reiner Strick,
  • Reiner Strick,
  • Reiner Strick,
  • Reiner Strick,
  • Danijel Sikic,
  • Danijel Sikic,
  • Danijel Sikic,
  • Danijel Sikic,
  • Sven Wach,
  • Sven Wach,
  • Sven Wach,
  • Sven Wach,
  • Helge Taubert,
  • Helge Taubert,
  • Helge Taubert,
  • Helge Taubert,
  • Bernd Wullich,
  • Bernd Wullich,
  • Bernd Wullich,
  • Bernd Wullich,
  • Arndt Hartmann,
  • Arndt Hartmann,
  • Arndt Hartmann,
  • Arndt Hartmann,
  • Barbara Seliger,
  • Barbara Seliger,
  • Markus Eckstein,
  • Markus Eckstein,
  • Markus Eckstein,
  • Markus Eckstein

DOI
https://doi.org/10.3389/fimmu.2024.1478196
Journal volume & issue
Vol. 15

Abstract

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IntroductionUrothelial bladder cancer is frequent and exhibits diverse prognoses influenced by molecular subtypes, urothelial subtype histology, and immune microenvironments. HLA-G, known for immune regulation, displays significant membranous expression in tumor tissues.MethodsWe studied the protein expression of Human Leucocyte Antigen G (HLA-G) in 241 Muscle-Invasive Bladder Cancer (MIBC) patients, elucidating its potential clinical and biological significance. Protein expression levels were evaluated and correlated with molecular subtypes, histological characteristics, immune microenvironment markers, and survival outcomes.ResultsHigh HLA-G expression associates with poor overall survival (OS) and diseasespecific survival (DSS), independent of clinicopathological parameters. HLA-G expression varies among molecular subtypes and Urothelial Subtype Histology, e.g., elevated expression levels in basal/squamous MIBC and those with sarcomatoid differentiation. Notably, HLA-G is increased in MIBC with an immune evasive microenvironment (high PD-L1 tumor cell expression, NK cell depletion, granzyme B (GZMB)/CD8 ratio reduction, MHC class I (MHCI) expression reduction) that are characterized by immunosuppressive features and poor prognosis. Furthermore, HLA-G correlates with elevated levels of other immune checkpoint proteins (TIGIT, LAG3, CTLA-4), indicating its role in immune evasion.DiscussionOur findings underscore HLA-G’s role as a potential prognostic marker and interesting immunotherapeutic target in MIBC. Its impact on immune evasion mechanisms and broad expression, coupled with associations withpoor survival and distinct tumor phenotypes, positions HLA-G as a promising protein for further exploration in developing targeted immunotherapies for MIBC patients.

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