Epidermal activation of Hedgehog signaling establishes an immunosuppressive microenvironment in basal cell carcinoma by modulating skin immunity. Issue 9 (21st July 2020)

• Record Type: Journal Article
• Authors: Grund‐Gröschke, Sandra; Ortner, Daniela; Szenes‐Nagy, Antal B.; Zaborsky, Nadja; Weiss, Richard; Neureiter, Daniel; Wipplinger, Martin; Risch, Angela; Hammerl, Peter; Greil, Richard; Sibilia, Maria; Gratz, Iris K.; Stoitzner, Patrizia; Aberger, Fritz
• Is Part Of: Molecular oncology. Volume 14:Issue 9(2020)
• Page Start: 1930
• Page End: 1946
• Publication Date: 2020-07-21
• Subjects: basal cell carcinoma -- cancer immunotherapy -- hedgehog/gli signaling -- immune checkpoint molecules -- neutrophils -- regulatory T cells; Cancer -- Molecular aspects -- Periodicals; 616.994005
• DOI: 10.1002/1878-0261.12758
• Languages: English
• ISSNs: 1574-7891

Abstract

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 . Abstract : Activation of hedgehog/glioma‐associated oncogene homolog (HH/GLI) signaling induces basal cell carcinoma (BCC) and establishes an immunosuppressive tumor microenvironment. HH/GLI signaling inhibits the activity of antitumoral T cells via programmed death ligand 1/programmed death‐1 immune checkpoint signaling and the recruitment of immunosuppressive regulatory T cells. BCCs also show strong infiltration with antitumoral neutrophils. The data support the evaluation of combination treatments with HH inhibitors and immune checkpoint blockers.