Wnt3a-expressing cancer stem cells impair CD8⁺ TRM function, contributing to immunotherapy resistance in Melanoma

Area of Science:

• Oncology
• Immunology
• Cancer Stem Cells

Background:

• Immune checkpoint blockade (ICB) shows promise in advanced melanoma, but many patients do not respond.
• Mechanisms of resistance to anti-PD-1 therapy, a key ICB, are not fully understood.

Purpose of the Study:

• To investigate the mechanisms of anti-PD-1 resistance in melanoma.
• To identify potential therapeutic targets to overcome ICB resistance.

Main Methods:

• Developed anti-PD-1 resistant murine melanoma cell lines (R1, R2).
• Assessed tumor initiation, invasiveness, and metastasis.
• Analyzed cancer stem cell (CSC) populations and T cell infiltration/function.
• Investigated Wnt/β-catenin signaling inhibition in vitro and in vivo.
• Performed transcriptomic analysis on public melanoma cohorts.

Main Results:

• Resistant melanoma cells showed increased tumor initiation, invasiveness, and metastasis.
• Enrichment of Wnt3a-overexpressing CSC-like populations correlated with reduced CD8+ tissue-resident memory (TRM) T cell infiltration and function.
• Wnt/β-catenin inhibition in vitro enhanced CD8+ T cell proliferation and function.
• In vivo Wnt/β-catenin inhibition reversed anti-PD-1 resistance, reduced CSCs, and restored CD8+ TRMs.
• Wnt pathway enrichment in human melanoma cohorts correlated with poor prognosis and ICB resistance.

Conclusions:

• Wnt/β-catenin signaling promotes cancer stemness and suppresses anti-tumor CD8+ T cell responses, contributing to anti-PD-1 resistance in melanoma.
• Targeting the Wnt pathway represents a potential strategy to enhance ICB efficacy in non-responsive melanoma patients.