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

Autor:	van Ravensteijn SG; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands., Amir AL; Department of Pathology, Radboud University Medical Center, Nijmegen, the Netherlands., Tauriello DVF; Department of Medical BioSciences, Radboud University Medical Center, Nijmegen, the Netherlands.; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands., van Herpen CML; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands., Boers-Sonderen MJ; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands., Wesseling YJW; InnoSIGN B.V. High Tech Campus 11, Eindhoven, the Netherlands., van Brussel AGC; InnoSIGN B.V. High Tech Campus 11, Eindhoven, the Netherlands., Keizer DM; InnoSIGN B.V. High Tech Campus 11, Eindhoven, the Netherlands., Verheul HMW; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.; Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center, Rotterdam, the Netherlands., Bol KF; Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
Jazyk:	angličtina
Zdroj:	Clinical and experimental immunology [Clin Exp Immunol] 2024 Nov 30. Date of Electronic Publication: 2024 Nov 30.
DOI:	10.1093/cei/uxae108
Abstrakt:	Introduction: Immune checkpoint inhibition (ICI) is highly effective for the treatment of melanoma, but intrinsic resistance is present in a subgroup of patients. TGF-β pathway activity may play a role in this resistance by preventing T-cells from entering the tumor microenvironment, causing immune escape. We investigated the association of TGF-β signal transduction pathway activity with resistance to ICI treatment in advanced melanoma. Furthermore, other pathway activities were analyzed to better understand their potential role in ICI resistance. Method: The activity of 8 signaling pathways (TGF-β, Hedgehog, MAPK, AR, NOTCH, PI3K, JAK/STAT1-2, and NFkB) was analyzed from tumor tissue from patients with advanced melanoma. Pathway activity scores (PAS) were explored for associations with survival and response to ICI in 34 patients (19 non-responders and 15 responders). A second, independent method to investigate the predictive value of TGF-β pathway activation was conducted by determining levels of phosphorylated SMAD2. Results: The mean TGF-β PAS of responders vs non-responders was 53.9 vs 56.8 (P = 0.265). No significant relation with progression-free survival was detected for TGF-β activity (P = 0.078). No association between pSMAD2 staining and treatment response or survival was identified. In contrast, Hedgehog scores of responders versus non-responders were 35.7 vs 41.6 (P = 0.038). High Hedgehog PAS was the sole significant predictor of resistance to ICI (OR 0.88, P = 0.033) and worse progression-free survival (HR 1-1.1, P = 0.012). Conclusion: TGF-β pathway activation showed no significant relation with treatment response to ICI or survival in patients with advanced melanoma. Hedgehog PAS was identified as a possible biomarker associated with both treatment response and survival. (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Immunology.)
Databáze:	MEDLINE
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