Abstract
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. 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. 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. 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.
Highlights
Advanced basal cell carcinomas (BCCs) are a small subset of Basal cell carcinoma (BCC) that cause significant morbidity and remain a therapeutic challenge due to their local invasiveness and proximity to vital structures [1]
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
We demonstrate that inhibition of the Hh pathway results in upregulated MHC class I expression on BCCs and attracts MHC class IIþ, CD4þ, and CD8þ T cells into the tumor www.aacrjournals.org
Summary
Advanced basal cell carcinomas (BCCs) are a small subset of BCCs that cause significant morbidity and remain a therapeutic challenge due to their local invasiveness and proximity to vital structures [1]. Despite the presence of cancer testis and other tumor antigens, BCCs escape from immune surveillance by the downregulation of HLA class I expression [2]. Targeted therapy based on knowledge of BCC pathogenesis has become available either commercially or in the context of human clinical trials. These orally available drugs, such as vismodegib and sonidegib, inhibit the Hedgehog (Hh) signaling pathway, and have improved the therapeutic repertoire [3,4,5,6]. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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