title: Hedgehog pathway inhibitors promote adaptive immune responses in basal cell carcinoma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Otsuka
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Jil
authors.initials: J
authors.lastname: Dreier
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Phil F
authors.initials: PF
authors.lastname: Cheng
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Nägeli
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Lehmann
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Lea
authors.initials: L
authors.lastname: Felderer
authors.affiliation: Institute of Physiology, University of Zurich, Zurich, Switzerland.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Frew
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. Department of Dermato-Oncology/Dermatology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Matsushita
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. reinhard.dummer@usz.ch mitchellpaul.levesque@usz.ch.
authors.forename: Mitchell P
authors.initials: MP
authors.lastname: Levesque
authors.affiliation: Department of Dermatology, University Hospital Zurich, Zurich, Switzerland. reinhard.dummer@usz.ch mitchellpaul.levesque@usz.ch.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects / Q000276:immunology*; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides / Q000627:therapeutic use; D001706:Biopsy; D001713:Biphenyl Compounds / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002923:Cilia / Q000187:drug effects / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006684:HLA-DR Antigens / Q000276:immunology; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D011725:Pyridines / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000072086:Smoothened Receptor; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D000813:Anilides; D001713:Biphenyl Compounds; D016207:Cytokines; D006684:HLA-DR Antigens; D053823:Hedgehog Proteins; C538724:HhAntag691; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C561435:sonidegib