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Clin Cancer Res. 2015 Mar 15;21(6):1289-97. doi: 10.1158/1078-0432.CCR-14-2110. Epub 2015 Jan 15.

Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma.

Author information

1
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
2
Institute of Physiology, University of Zurich, Zurich, Switzerland.
3
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. Department of Dermato-Oncology/Dermatology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.
4
Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. reinhard.dummer@usz.ch mitchellpaul.levesque@usz.ch.

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.

PMID:
25593302
DOI:
10.1158/1078-0432.CCR-14-2110
[Indexed for MEDLINE]
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