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Review
. 2023 Jan 10;24(2):1321.
doi: 10.3390/ijms24021321.

Emerging Roles of Hedgehog Signaling in Cancer Immunity

Alessandro Giammona  1 , Enrica Crivaro  1   2 , Barbara Stecca  1
Affiliations
Review

Emerging Roles of Hedgehog Signaling in Cancer Immunity

Alessandro Giammona et al. Int J Mol Sci. .

Abstract

Hedgehog-GLI (HH) signaling plays an essential role in embryogenesis and tissue homeostasis. Aberrant activation of the pathway through mutations or other mechanisms is involved in the development and progression of numerous types of cancer, including basal cell carcinoma, medulloblastoma, melanoma, breast, prostate, hepatocellular and pancreatic carcinomas. Activation of HH signaling sustains proliferation, suppresses cell death signals, enhances invasion and metastasis, deregulates cellular metabolism and promotes angiogenesis and tumor inflammation. Targeted inhibition of the HH pathway has therefore emerged as an attractive therapeutic strategy for the treatment of a wide range of cancers. Currently, the Smoothened (SMO) receptor and the downstream GLI transcriptional factors have been investigated for the development of targeted drugs. Recent studies have revealed that the HH signaling is also involved in tumor immune evasion and poor responses to cancer immunotherapy. Here we focus on the effects of HH signaling on the major cellular components of the adaptive and innate immune systems, and we present recent discoveries elucidating how the immunosuppressive function of the HH pathway is engaged by cancer cells to prevent immune surveillance. In addition, we discuss the future prospect of therapeutic options combining the HH pathway and immune checkpoint inhibitors.

Keywords: combination therapy; hedgehog signaling; immune checkpoint inhibitors; immune evasion; immunosuppression; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Canonical activation of HH signaling. When HH ligands are not present (A), PTCH1 represses SMO by preventing its entry into the primary cilium (PC). GLI2 and GLI3 are sequestered in the cytoplasm by SUFU and phosphorylated by PKA, CK1 and GSK3β. The GLI undergo ubiquitination through the E3 ubiquitin ligase β-TrCP. GLI1 is fully degraded, whereas GLI3 and, to a lesser extent, GLI2 undergo partial proteasome degradation, leading to the formation of repressor forms (GLI3/2R) that move into the nucleus inhibiting the transcription of GLI target genes. In the presence of HH ligands (B), PTCH1 is displaced from the PC and undergoes lysosomal degradation, and SMO translocates into the PC. Active SMO relieves the SUFU-mediated suppression of GLI2 and GLI3, triggering a signaling cascade that leads to the translocation of full length activated forms of GLI (GLIACT) into the nucleus, where they promote the transcription of GLI target genes. KIF7 is a kinesin protein that acts in anterograde transport (from base to tip) of the PC. CK1, casein kinase 1; GLI2/3R, GLI2/3 repressors; GLIACT, GLI activators; GLIFL, GLI full length; GSK3β, glycogen synthase kinase 3β; HH, Hedgehog; KIF7, kinesin family member 7; PKA, protein kinase A; PTCH1, Patched 1; SMO, Smoothened; SUFU, Suppressor of Fused; β-TrCP, β-transducin repeat-containing protein.
Figure 2
Figure 2
Impact of HH signaling on the immune tumor microenvironment. The HH pathway is active in cancer cells and in several other cell types present in the tumor microenvironment, including TAM, T Reg and fibroblasts. (1) Cancer cells release SHH, driving the polarization of M2 macrophages and repressing M1 macrophages. M2 polarization is mediated by KLF4, which is transcriptionally regulated by GLI1. (2) HH-induced polarization of TAMs suppresses CD8+ T cell recruitment through the inhibition of CXCL9 and CXCL10. (3) HH signaling regulates the immunosuppressive metabolism in M2 TAMs by increasing the UDP-GlcNAc (uridine diphosphate-N-acetylglucosamine) biosynthesis pathway, fatty acid oxidation (FAO) and oxidative phosphorylation (OXPHOS). (4) HH-induced PDL1 expression in cancer cells inhibits tumor-specific CD8+ T cells via binding to PD1. (5) HH-induced TGFβ activates the CCL2/CCR2 axis to recruit immunosuppressive MDSCs in BCC. (6) Fibroblast-specific ablation of Gli2/Gli3 decreases the recruitment of MDSCs and increases NK cells suppressing tumor growth in PDA. (7) Cancer-secreted SHH activates HH signaling in surrounding myCAFs in PDA. (8) GLI2 drives the production of immunosuppressive cytokines and growth factors (IL-10 and TGFβ) which results in the inactivation of tumor-specific CD8+ T cells. (9) HH activation decreases the recruitment of DCs.
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References

    1. Ingham P.W., McMahon A.P. Hedgehog signaling in animal development: Paradigms and principles. Genes Dev. 2001;15:3059–3087. doi: 10.1101/gad.938601. - DOI - PubMed
    1. Hanna A., Shevde L.A. Hedgehog signaling: Modulation of cancer properties and tumor microenvironment. Mol. Cancer. 2016;15:24. doi: 10.1186/s12943-016-0509-3. - DOI - PMC - PubMed
    1. Grund-Gröschke S., Stockmaier G., Aberger F. Hedgehog/GLI signaling in tumor immunity—New therapeutic opportunities and clinical implications. Cell Commun. Signal. 2019;17:172. doi: 10.1186/s12964-019-0459-7. - DOI - PMC - PubMed
    1. Varjosalo M., Taipale J. Hedgehog: Functions and mechanisms. Genes Dev. 2008;22:2454–2472. doi: 10.1101/gad.1693608. - DOI - PubMed
    1. Montagnani V., Stecca B. Role of Protein Kinases in Hedgehog Pathway Control and Implications for Cancer Therapy. Cancers. 2019;11:449. doi: 10.3390/cancers11040449. - DOI - PMC - PubMed