Abstract
Simple SummaryWnt and Hedgehog (Hh) pathways are associated with stemness profile and with resistance to anti-tumor therapies. Pre-clinical data have suggested a role of these pathways in resistance to immune checkpoint inhibitors (ICIs). Here we evaluated the expression and levels of Shh and Wnt molecules both in plasma and tumor samples in a prospective cohort of 63 consecutive NSCLC patients treated with ICIs. We found that baseline Hh activation as assessed by nuclear staining of Gli1 was associated with poor outcome and high primary resistance rate. Increase of plasma Wnt1 during treatment was associated with resistance to ICIs. This is the first study to our knowledge to find an association between the Hh and Wnt pathways and resistance to ICIs in advanced NSCLC patients. We believe that these results are important to understand the molecular mechanisms associated with resistance to ICIs, and ultimately to improve future treatment strategies.Hedgehog (Hh) and Wingless-type (Wnt) pathways are associated with resistance to immune checkpoint inhibitors (ICIs) in preclinical studies. This study aimed to assess the association between expression and activation levels of Wnt and Sonic Hedgehog (Shh) pathways and resistance to ICIs in advanced NSCLC patients treated with ICI. Hh and Wnt pathways activation was assessed by immunohistochemistry (Gli1 and beta-catenin) on corresponding tumor tissues, and by plasma concentrations of Shh and Wnt (Wnt1, Wnt2 and Wnt3) at ICI introduction and at the first clinical evaluation. Sixty-three patients were included, with 36 patients (57.1%) with available tissue. Response rate was lower in Gli1+ NSCLC (20.0%) compared to Gli1 negative (Gli-) NSCLC (55.6%) (p = 0.015). Rate of primary resistance was 69.8%, vs. 31.2%, respectively (p = 0.04), and median progression-free survival (PFS) was 1.9 months (interquartile range (IQR) 1.2–5.7) vs. 6.1 months (1.6–26.0), respectively (p = 0.08). Median PFS and overall survival were shorter in case of increase of Wnt1 concentration during ICI treatment compared to other patients: 3.9 months vs. 11.2 months (p = 0.008), and 15.3 months vs. not reached (p = 0.003). In conclusion, baseline activation of Hh pathway and increase of Wnt1 concentrations during ICI treatment were associated with poor outcome in NSCLC patients treated with ICIs.
Highlights
Immune checkpoints inhibitors (ICIs) can restore anti-tumor immunity, notably by disrupting the immune checkpoint axis between cytotoxic T-lymphocytes and tumor cells, through the target of immune checkpoint molecules such as PD-1/PD-L1 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4)
No significant result was observed for Objective response rate (ORR), primary resistance, progression-free survival (PFS) and overall survival (OS) according to Wnt3 concentrations
We found that baseline activation of Sonic Hedgehog (Shh) pathway and increase of Wnt1 during ICI treatment were associated with poor outcome in non-small cell lung cancer (NSCLC) patients treated with
Summary
Immune checkpoints inhibitors (ICIs) can restore anti-tumor immunity, notably by disrupting the immune checkpoint axis between cytotoxic T-lymphocytes and tumor cells, through the target of immune checkpoint molecules such as PD-1 (programmed death-1)/PD-L1 (programmed death-ligand 1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Wnt signaling is activated when Wnt ligands bind to the receptors of the Frizzled family, leading to the stabilization of beta-catenin and its nuclear accumulation, that will trigger the expression of genes involved in cell survival and proliferation [17]. Wnt pathway activation were found associated with reduced antitumoral immunity The latter is characterized by low peritumoral lymphocyte infiltration, especially in melanoma and hepatocarcinoma, and presumably with lower ICIs efficacy [21,22,23]. Hh pathway is activated when hedgehog ligands such as Sonic Hedgehog (Shh), Indian Hedgehog (Ihh) or Desert Hedgehog (Dhh), bind on the Patched receptor, orchestrating the nuclear localization of Gli proteins (Gli1-3), triggering gene expression.
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