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Review
. 2019 Dec 26;17(1):172.
doi: 10.1186/s12964-019-0459-7.

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

Sandra Grund-Gröschke  1 , Georg Stockmaier  1 , Fritz Aberger  2
Affiliations
Review

Hedgehog/GLI signaling in tumor immunity - new therapeutic opportunities and clinical implications

Sandra Grund-Gröschke et al. Cell Commun Signal. .

Abstract

Uncontrolled activation of the Hedgehog/Glioma-associated oncogene (HH/GLI) pathway is a potent oncogenic driver signal promoting numerous cancer hallmarks such as proliferation, survival, angiogenesis, metastasis and metabolic rewiring. Several HH pathway inhibitors have already been approved for medical therapy of advanced and metastatic basal cell carcinoma and acute myeloid leukemia with partially impressive therapeutic activity. However, de novo and acquired resistance as well as severe side effects and unexplained lack of therapeutic efficacy are major challenges that urgently call for improved treatment options with more durable responses. The recent breakthroughs in cancer immunotherapy have changed our current understanding of targeted therapy and opened up promising therapeutic opportunities including combinations of selective cancer pathway and immune checkpoint inhibitors. Although HH/GLI signaling has been intensely studied with respect to the classical hallmarks of cancer, its role in the modulation of the anti-tumoral immune response has only become evident in recent studies. These have uncovered HH/GLI regulated immunosuppressive mechanisms such as enhanced regulatory T-cell formation and production of immunosuppressive cytokines. In light of these exciting novel data on oncogenic HH/GLI signaling in immune cross-talk and modulation, we summarize and connect in this review the existing knowledge from different HH-related cancers and chronic inflammatory diseases. This is to provide a basis for the investigation and evaluation of novel treatments combining immunotherapeutic strategies with approved as well as next-generation HH/GLI inhibitors. Further, we also critically discuss recent studies demonstrating a possible negative impact of current HH/GLI pathway inhibitors on the anti-tumoral immune response, which may explain some of the disappointing results of several oncological trials with anti-HH drugs. Additional file 1Video abstract. (9500 kb).

Keywords: Cancer immunotherapy; Chronic inflammation; Combination therapy; Immune checkpoint inhibitors; Immune evasion; Immunosuppression; Oncogenic Hedgehog/GLI signaling; Tumor microenvironment.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Mechanisms of immune modulation by HH/GLI signaling in cancer and inflammation. 1) Cancer cells release CCL2/3 in response to oncogenic HH/GLI signaling, thereby recruiting TAMs and immunosuppressive MDSCs. 2) HH/GLI-induced PD-L1 expression in cancer and dendritic cells inhibits tumor specific cytotoxic T-cells via binding to PD-1. 3) GLI2 drives production of immunosuppressive cytokines and growth factors (IL10 and TGFβ), which results in the inactivation of tumor specific CD8+ T-cells. 4) HH/GLI-induced IL10 from stromal cells promotes FoxP3 expression in regulatory T-cells. 5) Pro-inflammatory signals such as IL6/STAT3 interact with HH/GLI signaling; HH/GLI-induced autocrine IL6 signaling and/or pro-inflammatory IL6 from TAM and stromal cells activate STAT3 signaling in cancer cells, thereby promoting malignant growth
Fig. 2
Fig. 2
Possible rational combination treatments for HH/GLI-associated cancers simultaneously targeting HH/GLI and HH-regulated immunosuppressive and tumor-promoting signals. The efficacy, response rate and durability of the therapeutic effect of HH/GLI pathway inhibition is likely to increase upon combination of approved HH/SMO antagonists with small molecules and/or biologics such as neutralizing or blocking antibodies developed for the selective inhibition of immune suppression and tumor-promoting inflammation
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