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Hedgehog Pathway Inhibitors Promote Adaptive Immune Responses in Basal Cell Carcinoma
Open accessPublished version of a preprint
Abstract
PURPOSE: Basal cell carcinomas (BCCs) are tumors ignored by immune surveillance. Activated Hedgehog (Hh) signaling within primary cilia is a key driver in the pathogenesis of BCCs. We examined immune alterations during treatment with systemic Hh inhibitors. EXPERIMENTAL DESIGN: We investigated biopsies from patients with BCC before (23 patients) and after 4 weeks of treatment (5 patients) with Hh signaling inhibitor. Ber-Ep4, BCL-2, Ki-67, CD4, CD8, MHC class I, HLA-DR-class II, and SOX9 were analyzed by immunohistochemistry. Primary cilia were analyzed by double immunofluorescence of acetylated tubulin and SOX9. Differential gene expression for 84 cytokines and chemokines was analyzed in 3 patients. RESULTS: After 4 weeks of treatment, we found reduction of Ki-67, SOX9, Ber-EP4, and BCL-2 expression in tumors associated with morphologic signs of squamous differentiation. In addition, the number of cilia-positive BCC cells was significantly decreased. An upregulation of MHC I expression on the cell membranes of residual tumor cells and an influx of CD4(+), HLA-DR-class II(+), and CD8(+) cells with invasion into the tumor cell nests were found. Finally, qPCR arrays showed the differential expression of genes involved in modulating immune responses. CONCLUSIONS: We show that Hh pathway inhibitor-induced tumor regression is accompanied by a dynamic change of the microenvironment with a disruption of immune privilege involving an influx of cytotoxic T cells, activation of the adaptive immune functions, and a profound alteration of the local chemokine/cytokine network.
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“Tumor cells may evade immune recognition directly by downregulating features that make them vulnerable such as tumor antigens or MHC class I (4–6).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [4]
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Metadata
- Authors
- Otsuka, A., Dreier, J., Cheng, P. F., Nägeli, M., Lehmann, H., Felderer, L., Frew, I. J., Matsushita, S., Levesque, M. P., & Dummer, R.
- Affiliations
- University Hospital Zurich (CH)
- University of Zurich (CH)
- Corresponding author
- Levesque, Mitchell P.
- Dummer, Reinhard
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2015-03-12
- Volume
- 21
- Issue
- 6
- Pages
- 1289-1297
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- OpenAlex
- W2153635433
- Cited by
- 106
- References
- 33
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 14 · 2022: 13 · 2021: 13 · 2020: 12 · 2019: 12 · 2018: 10 · 2017: 5 · 2016: 7 · 2015: 3
- FWCI
- 3.61
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, other-oa)
- Zurich Open Repository and Archive (University of Zurich)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Dermatology › Nonmelanoma Skin Cancer Studies
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Keywords
- basal cell carcinoma, Hedgehog pathway inhibitors, adaptive immune response, primary cilia, tumor immune microenvironment, MHC class I expression, CD8+ cytotoxic T lymphocytes, CD4+ T cells, HLA-DR, SOX9, tumor regression, squamous differentiation, immune privilege
- MeSH terms
- Smoothened Receptor, Aged, Aged, 80 and over, Anilides, Biopsy, Biphenyl Compounds, Basal Cell Carcinoma, Cilia, Female, HLA-DR Antigens, Humans, Lymphocyte Activation, Male, Middle Aged, Pyridines, Skin Neoplasms, T-Lymphocytes, Cytotoxic, Signal Transduction, CD4-Positive T-Lymphocytes, Cytokines, Receptors, G-Protein-Coupled, Hedgehog Proteins, Adaptive Immunity
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