Age-related decline in CD8+ tissue resident memory T cells compromises antitumor immunity

Nat Aging. 2024 Dec;4(12):1828-1844. doi: 10.1038/s43587-024-00746-5. Epub 2024 Nov 26.

Abstract

Aging compromises antitumor immunity, but the underlying mechanisms remain elusive. Here, we report that aging impairs the generation of CD8+ tissue resident memory T (TRM) cells in nonlymphoid tissues in mice, thus compromising the antitumor activity of aged CD8+ T cells, which we also observed in human lung adenocarcinoma. We further identified that the apoptosis regulator BFAR was highly enriched in aged CD8+ T cells, in which BFAR suppressed cytokine-induced JAK2 signaling by activating JAK2 deubiquitination, thereby limiting downstream STAT1-mediated TRM reprogramming. Targeting BFAR either through Bfar knockout or treatment with our developed BFAR inhibitor, iBFAR2, rescued the antitumor activity of aged CD8+ T cells by restoring TRM generation in the tumor microenvironment, thus efficiently inhibiting tumor growth in aged CD8+ T cell transfer and anti-programmed cell death protein 1 (PD-1)-resistant mouse tumor models. Together, our findings establish BFAR-induced TRM restriction as a key mechanism causing aged CD8+ T cell dysfunction and highlight the translational potential of iBFAR2 in restoring antitumor activity in aged individuals or patients resistant to anti-PD-1 therapy.

MeSH terms

  • Adenocarcinoma of Lung / genetics
  • Adenocarcinoma of Lung / immunology
  • Adenocarcinoma of Lung / pathology
  • Aging* / immunology
  • Animals
  • CD8-Positive T-Lymphocytes* / drug effects
  • CD8-Positive T-Lymphocytes* / immunology
  • Cell Line, Tumor
  • Humans
  • Immunologic Memory / drug effects
  • Janus Kinase 2 / metabolism
  • Lung Neoplasms / immunology
  • Lung Neoplasms / pathology
  • Memory T Cells* / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Tumor Microenvironment / immunology

Substances

  • Janus Kinase 2
  • STAT1 Transcription Factor
  • Jak2 protein, mouse