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FGFR1/MAPK-directed brachyury activation drives PD-L1-mediated immune evasion to promote lung cancer progression

Yunping Hu1, Yong Lu2, Fei Xing3

  • 1Department of Neurological Surgery, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157, USA.

Cancer Letters
|August 19, 2022
PubMed

Insights

Brachyury activation in lung cancer drives resistance to immune checkpoint inhibitors by upregulating PD-L1. Targeting FGFR1/MAPK signaling can overcome this resistance, improving therapeutic responses and patient survival.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint inhibitors (ICIs) show promise in cancer treatment but face significant resistance.
  • Tumor-mediated resistance mechanisms are critical to understand for improving ICI efficacy.
  • Brachyury, a transcription factor, is upregulated in lung cancer and linked to poor outcomes.

Purpose of the Study:

  • To elucidate the role of brachyury in tumor resistance to ICIs.
  • To investigate the FGFR1/MAPK signaling pathway in regulating brachyury and PD-L1 expression.
  • To evaluate the therapeutic potential of targeting this pathway in lung cancer.

Main Methods:

  • In vitro assays assessing T cell proliferation and activation.
  • In vivo studies using immunocompetent mouse models of lung cancer.
  • Analysis of patient data correlating molecular signatures with survival outcomes.

Main Results:

  • Brachyury activation upregulates PD-L1, inhibiting T cell proliferation and infiltration.
  • FGFR1/MAPK signaling drives brachyury and PD-L1 expression, promoting immunosuppression.
  • Blocking FGFR1/MAPK restores immune activity and reverses resistance to anti-PD-1 therapy.
  • High FGFR1-MAPK-brachyury-PD-L1 signature with low CD8A/CD3D/PDCD1 expression correlates with worse patient survival.

Conclusions:

  • Brachyury-PD-L1 axis mediated by FGFR1/MAPK is a novel mechanism of immune escape in lung cancer.
  • Targeting FGFR1/MAPK offers a strategy to enhance ICI efficacy in a subset of lung cancers.
  • This pathway presents a potential therapeutic target for improving patient survival in FGFR1/MAPK/brachyury/PD-L1-driven lung cancer.
Keywords:
BrachyuryFibroblast growth factor receptor 1Lung cancerMitogen-activated protein kinasePD-L1

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