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Updated: Jun 5, 2025

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Exploring the relation between TGF-β pathway activity and response to checkpoint inhibition in patients with

Stefan G van Ravensteijn1, Avital L Amir2, Daniele V F Tauriello3,4

  • 1Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.

Clinical and Experimental Immunology
|December 12, 2024
PubMed
Abstract

Insights

Immune checkpoint inhibition (ICI) is a melanoma treatment, but resistance occurs. The TGF-β pathway did not predict resistance, but the Hedgehog pathway did, indicating its potential as a biomarker for ICI response and survival in advanced melanoma.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Immune checkpoint inhibition (ICI) offers effective melanoma treatment.
  • Intrinsic resistance to ICI affects a subset of patients.
  • Transforming growth factor-beta (TGF-β) pathway activity is implicated in immune escape and ICI resistance.

Purpose of the Study:

  • To investigate the association between TGF-β pathway activity and resistance to ICI in advanced melanoma.
  • To analyze other signaling pathway activities for their role in ICI resistance.
  • To identify potential biomarkers for predicting ICI treatment outcomes.

Main Methods:

  • Analyzed activity of 8 signaling pathways (including TGF-β and Hedgehog) in tumor tissue from 34 advanced melanoma patients.
  • Assessed pathway activity scores (PAS) for associations with survival and ICI response.
  • Utilized phosphorylated SMAD2 (pSMAD2) levels as an independent measure of TGF-β pathway activation.

Main Results:

  • No significant association was found between TGF-β pathway activity (PAS or pSMAD2) and ICI treatment response or progression-free survival.
  • Hedgehog pathway activity scores were significantly lower in responders compared to non-responders (P=0.038).
  • High Hedgehog PAS was identified as a significant predictor of resistance to ICI (OR 0.88, P=0.033) and worse progression-free survival (HR 1-1.1, P=0.012).

Conclusions:

  • TGF-β pathway activation is not significantly related to treatment response or survival in advanced melanoma patients receiving ICI.
  • Hedgehog pathway activity shows potential as a predictive biomarker for both ICI treatment response and patient survival.
  • Further research into the Hedgehog pathway's role could lead to improved therapeutic strategies for melanoma.
Keywords:
TGF-betabiomarkerimmunotherapymelanoma

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