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

Mol Oncol. 2020 Sep;14(9):1930-1946. doi: 10.1002/1878-0261.12758. Epub 2020 Jul 21.

Abstract

Genetic activation of hedgehog/glioma-associated oncogene homolog (HH/GLI) signaling causes basal cell carcinoma (BCC), a very frequent nonmelanoma skin cancer. Small molecule targeting of the essential HH effector Smoothened (SMO) has proven an effective therapy of BCC, though the frequent development of drug resistance poses major challenges to anti-HH treatments. In light of recent breakthroughs in cancer immunotherapy, we analyzed the possible immunosuppressive mechanisms in HH/GLI-induced BCC in detail. Using a genetic mouse model of BCC, we identified profound differences in the infiltration of BCC lesions with cells of the adaptive and innate immune system. Epidermal activation of Hh/Gli signaling led to an accumulation of immunosuppressive regulatory T cells, and to an increased expression of immune checkpoint molecules including programmed death (PD)-1/PD-ligand 1. Anti-PD-1 monotherapy, however, did not reduce tumor growth, presumably due to the lack of immunogenic mutations in common BCC mouse models, as shown by whole-exome sequencing. BCC lesions also displayed a marked infiltration with neutrophils, the depletion of which unexpectedly promoted BCC growth. The study provides a comprehensive survey of and novel insights into the immune status of murine BCC and serves as a basis for the design of efficacious rational combination treatments. This study also underlines the need for predictive immunogenic mouse models of BCC to evaluate the efficacy of immunotherapeutic strategies in vivo.

Keywords: basal cell carcinoma; cancer immunotherapy; hedgehog/gli signaling; immune checkpoint molecules; neutrophils; regulatory T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Basal Cell / immunology*
  • Carcinoma, Basal Cell / pathology
  • Cell Proliferation
  • Chemokines / metabolism
  • Epidermis / pathology*
  • Hedgehog Proteins / metabolism*
  • Immune Checkpoint Proteins / metabolism
  • Immunity*
  • Immunosuppression*
  • Mice
  • Neutrophils / metabolism
  • Oncogenes
  • Signal Transduction*
  • Skin Neoplasms / immunology*
  • Skin Neoplasms / pathology
  • T-Lymphocytes / immunology
  • Tumor Microenvironment / immunology*
  • Zinc Finger Protein GLI1 / metabolism

Substances

  • Chemokines
  • Hedgehog Proteins
  • Immune Checkpoint Proteins
  • Zinc Finger Protein GLI1