Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Grund-Gröschke, Sandra; Ortner, Daniela; Szenes-Nagy, A.B.; Zaborsky, Nadja; Weiss, Richard; Neureiter, Daniel; Wipplinger, Martin; Risch, Angela; Hammerl, Peter; Greil, Richard; Sibilia, Maria; Gratz, Iris K.; Stoitzner, Patrizia; Aberger, Fritz

doi:10.1002/1878-0261.12758

Cited by 25 publications

(27 citation statements)

References 77 publications

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“…Hh and canonical or non-canonical Wnt signaling induce the expression and activation of immune checkpoint molecules such as PD-1/PDL-1 and CTLA-4 on CD8+ T cells. Thus, studies suggest that Shh and Wnt pathways support resistance to ICIs by maintaining the expression and activation of immune checkpoint molecules [ 31 , 34 , 36 ].…”

Section: Discussionmentioning

confidence: 99%

“…Notably, our group and others have previously demonstrated that Shh pathway is associated with resistance to several anti-tumor therapies [ 26 ] such as chemotherapy [ 27 , 28 ], Tyrosine Kinase Inhibitors (TKIs) [ 29 ] and radiotherapy [ 30 ]. Like Wnt signaling, Shh pathway is also involved in the development and the activation of the immune response [ 31 , 32 , 33 ]. In gastric cancer, hedgehog signaling supports the expression of PD-L1 and tumor cell proliferation [ 34 ].…”

Section: Introductionmentioning

confidence: 99%

“…Concordantly, growing evidence from pre-clinical studies have also suggested a lower efficacy of ICIs in case of Shh pathway activation in other cancers [ 32 , 33 , 35 ]. For example, in basal cell carcinoma, where the pathway is highly active, Hedgehog signaling inhibits cytotoxic T cells via the expression of PD-1 and the recruitment of immunosuppressive regulatory T cells [ 31 ].…”

Section: Introductionmentioning

confidence: 99%

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Baseline Hedgehog Pathway Activation and Increase of Plasma Wnt1 Protein Are Associated with Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer

Mehlman

Kamga

Costantini

et al. 2021

Cancers

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Baseline Hedgehog Pathway Activation and Increase of Plasma Wnt1 Protein Are Associated with Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer

Mehlman

Kamga

Costantini

et al. 2021

Cancers

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“…According to previously described ( 21 ), IHC and the immunoreactive score of SLC1A4 (proteintech, 13067-2-AP, 1:100) were conducted on the formalin-fixed and paraffin-embedded tissue sections.…”

Section: Methodsmentioning

confidence: 99%

SLC1A4: A Powerful Prognostic Marker and Promising Therapeutic Target for HCC

Chen

Cai

et al. 2021

Front. Oncol.

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SLC1A4, a Na-dependent neutral amino acid transporter, was considered to participate in the various pathobiological process, including tumorigenesis. However, the correlation between SLC1A4 and Hepatocellular Carcinoma (HCC) remains unclear. In our study, integrative bioinformatics and functional profiling were performed to reveal the prognosis and potential function of SLC1A4 in HCC. The results showed that the mRNA and protein levels of SLC1A4 were elevated in HCC, and it was a powerful independent prognostic marker for overall survival (OS). The co-expressed genes analysis and GSEA analysis showed that SLC1A4 was related to cell cycle, metabolism, cancer-related pathway. Furthermore, the functional analysis revealed that silenced SLC1A4 inhibited cell proliferation, migration, cell cycle, and promoted cell apoptosis in HCC. Next, immune analysis showed that SLC1A4 expression was positively associated with immune infiltration and immune-related chemokine expression in HCC. Silenced SLC1A4 evidently reduced these chemokines expression in HCC cells. Finally, drug sensitivity analysis revealed potential five sensitivity drugs for HCC patients with high-expressed SLC1A4. In conclusion, our results suggested that SLCIA4 could be a novel predictor prognosis and immunotherapeutic targets of HCC, and the sensitivity drugs may be effective therapeutic strategy for HCC patients with high-expressed SLC1A4.

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“…In naïve T-cells, Hh pathway activation again reduces TCR signaling to inhibit proliferation and activation on TCR/CD28 ligation (9,11,12), but also influences many aspects of T-cell differentiation. In addition to promoting CD4+ Th2 effector differentiation in vitro and in allergic airways disease (4, 10), Hh signaling has been shown to drive CD8+ cytotoxic T cell (CTL) differentiation in vitro (13) and to promote NKgd T-cell differentiation and CD4+ regulatory T-cell (Treg) differentiation and function in vivo and in vitro (14)(15)(16)(26)(27)(28). Consistent with its role in Tregs, in many tissues Hh signaling has been shown to have anti-inflammatory action (15,(29)(30)(31)(32)(33)(34)(35), in contrast to its well-known pro-inflammatory role in allergic asthma (2)(3)(4)(5)(6)(7)(8).…”

Section: Introductionmentioning

confidence: 99%

Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease

et al. 2021

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Allergic asthma is a common inflammatory airway disease in which Th2 immune response and inflammation are thought to be triggered by inhalation of environmental allergens. Many studies using mouse models and human tissues and genome-wide association have indicated that Sonic Hedgehog (Shh) and the Hedgehog (Hh) signaling pathway are involved in allergic asthma and that Shh is upregulated in the lung on disease induction. We used a papain-induced mouse model of allergic airway inflammation to investigate the impact of systemic pharmacological inhibition of the Hh signal transduction molecule smoothened on allergic airway disease induction and severity. Smoothened-inhibitor treatment reduced the induction of Shh, IL-4, and IL-13 in the lung and decreased serum IgE, as well as the expression of Smo, Il4, Il13, and the mucin gene Muc5ac in lung tissue. Smoothened inhibitor treatment reduced cellular infiltration of eosinophils, mast cells, basophils, and CD4+ T-cells to the lung, and eosinophils and CD4+ T-cells in the bronchoalveolar lavage. In the mediastinal lymph nodes, smoothened inhibitor treatment reduced the number of CD4+ T-cells, and the cell surface expression of Th2 markers ST2 and IL-4rα and expression of Th2 cytokines. Thus, overall pharmacological smoothened inhibition attenuated T-cell infiltration to the lung and Th2 function and reduced disease severity and inflammation in the airway.

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Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity

Cited by 25 publications

References 77 publications

Baseline Hedgehog Pathway Activation and Increase of Plasma Wnt1 Protein Are Associated with Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer

Baseline Hedgehog Pathway Activation and Increase of Plasma Wnt1 Protein Are Associated with Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer

SLC1A4: A Powerful Prognostic Marker and Promising Therapeutic Target for HCC

Systemic Pharmacological Smoothened Inhibition Reduces Lung T-Cell Infiltration and Ameliorates Th2 Inflammation in a Mouse Model of Allergic Airway Disease

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