Hypoxia-induced ZEB1 Promotes Cervical Cancer Immune Evasion by Strengthening the CD47-SIRPα Axis

Overview

Journal Cell Commun Signal

Publisher Biomed Central

Specialties Biochemistry
Cell Biology

Date 2024 Jan 5

PMID 38183060

Authors

Xiao-Jing Chen

Chu-Hong Guo

Zi-Ci Wang

Yang Yang

Yu-Hua Pan

Jie-Ying Liang

Mei-Ge Sun

Liang-Sheng Fan

Li Liang

Wei Wang

Affiliations

Soon will be listed here.

Abstract

Background: The dynamic interaction between cancer cells and tumour-associated macrophages (TAMs) in the hypoxic tumour microenvironment (TME) is an active barrier to the effector arm of the antitumour immune response. Cancer-secreted exosomes are emerging mediators of this cancer-stromal cross-talk in the TME; however, the mechanisms underlying this interaction remain unclear.

Methods: Exosomes were isolated with ExoQuick exosome precipitation solution. The polarizing effect of TAMs was evaluated by flow cytometry, western blot analysis, immunofluorescence staining and in vitro phagocytosis assays. Clinical cervical cancer specimens and an in vivo xenograft model were also employed.

Results: Our previous study showed that hypoxia increased the expression of ZEB1 in cervical squamous cell carcinoma (CSCC) cells, which resulted in increased infiltration of TAMs. Here, we found that hypoxia-induced ZEB1 expression is closely correlated with CD47-SIRPα axis activity in CSCC, which enables cancer cells to evade phagocytosis by macrophages and promotes tumour progression. ZEB1 was found to directly activate the transcription of the CD47 gene in hypoxic CSCC cells. We further showed that endogenous ZEB1 was characteristically enriched in hypoxic CSCC cell-derived exosomes and transferred into macrophages via these exosomes to promote SIRPα TAM polarization. Intriguingly, exosomal ZEB1 retained transcriptional activity and reprogrammed SIRPα TAMs via activation of the STAT3 signalling pathway in vitro and in vivo. STAT3 inhibition reduced the polarizing effect induced by exosomal ZEB1. Knockdown of ZEB1 increased the phagocytosis of CSCC cells by macrophages via decreasing CD47 and SIRPα expression.

Conclusions: Our results suggest that hypoxia-induced ZEB1 promotes immune evasion in CSCC by strengthening the CD47-SIRPα axis. ZEB1-targeted therapy in combination with CD47-SIRPα checkpoint immunotherapy may improve the outcomes of CSCC patients in part by disinhibiting innate immunity.

Citing Articles

Pathways and outputs orchestrated in tumor microenvironment cells by hypoxia-induced tumor-derived exosomes in pan-cancer.

Capik O, Karatas O Cell Oncol (Dordr). 2025; .

PMID: 39928285 DOI: 10.1007/s13402-025-01042-z.

The role and research progress of tumor-associated macrophages in cervical cancer.

Wang D, Han X, Liu H Am J Cancer Res. 2025; 14(12):5999-6011.

PMID: 39803646 PMC: 11711540. DOI: 10.62347/FFXL7288.

Therapeutic Potential of IL-37 in Cervical Cancer: Suppression of Tumour Progression and Enhancement of CD47-Mediated Macrophage Phagocytosis.

Feng Y, Feng L, Wang B, Zhang T, Cui B Mol Carcinog. 2024; 64(3):425-439.

PMID: 39620401 PMC: 11814915. DOI: 10.1002/mc.23855.

Exosomes are the mediators between the tumor microenvironment and prostate cancer (Review).

Wu Y, Wang X, Zeng Y, Liu X Exp Ther Med. 2024; 28(6):439.

PMID: 39355518 PMC: 11443591. DOI: 10.3892/etm.2024.12728.

How oxygenation shapes immune responses: emerging roles for physioxia and pathological hypoxia.

Mirchandani A, Sanchez-Garcia M, Walmsley S Nat Rev Immunol. 2024; 25(3):161-177.

PMID: 39349943 DOI: 10.1038/s41577-024-01087-5.

References

Andrechak J, Dooling L, Discher D . The macrophage checkpoint CD47 : SIRPα for recognition of 'self' cells: from clinical trials of blocking antibodies to mechanobiological fundamentals. Philos Trans R Soc Lond B Biol Sci. 2019; 374(1779):20180217. PMC: 6627025. DOI: 10.1098/rstb.2018.0217. View

Zhou C, Zhang Y, Yan R, Huang L, Mellor A, Yang Y . Exosome-derived miR-142-5p remodels lymphatic vessels and induces IDO to promote immune privilege in the tumour microenvironment. Cell Death Differ. 2020; 28(2):715-729. PMC: 7862304. DOI: 10.1038/s41418-020-00618-6. View

Gauttier V, Pengam S, Durand J, Biteau K, Mary C, Morello A . Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance. J Clin Invest. 2020; 130(11):6109-6123. PMC: 7598080. DOI: 10.1172/JCI135528. View

Guan T, Dominguez C, Amezquita R, Laidlaw B, Cheng J, Henao-Mejia J . ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8 T cell fates. J Exp Med. 2018; 215(4):1153-1168. PMC: 5881466. DOI: 10.1084/jem.20171352. View

Logtenberg M, Scheeren F, Schumacher T . The CD47-SIRPα Immune Checkpoint. Immunity. 2020; 52(5):742-752. PMC: 7340539. DOI: 10.1016/j.immuni.2020.04.011. View

Zhou C, Wei W, Ma J, Yang Y, Liang L, Zhang Y . Cancer-secreted exosomal miR-1468-5p promotes tumor immune escape via the immunosuppressive reprogramming of lymphatic vessels. Mol Ther. 2021; 29(4):1512-1528. PMC: 8058488. DOI: 10.1016/j.ymthe.2020.12.034. View

Barash U, Lapidot M, Zohar Y, Loomis C, Moreira A, Feld S . Involvement of Heparanase in the Pathogenesis of Mesothelioma: Basic Aspects and Clinical Applications. J Natl Cancer Inst. 2018; 110(10):1102-1114. PMC: 6186523. DOI: 10.1093/jnci/djy032. View

Nobre A, Entenberg D, Wang Y, Condeelis J, Aguirre-Ghiso J . The Different Routes to Metastasis via Hypoxia-Regulated Programs. Trends Cell Biol. 2018; 28(11):941-956. PMC: 6214449. DOI: 10.1016/j.tcb.2018.06.008. View

Huang Y, Du K, Guo P, Zhao R, Wang B, Zhao X . IL-16 regulates macrophage polarization as a target gene of mir-145-3p. Mol Immunol. 2019; 107:1-9. DOI: 10.1016/j.molimm.2018.12.027. View

10.

Kumar A, Deep G . Hypoxia in tumor microenvironment regulates exosome biogenesis: Molecular mechanisms and translational opportunities. Cancer Lett. 2020; 479:23-30. DOI: 10.1016/j.canlet.2020.03.017. View

11.

Chen Q, Wang C, Zhang X, Chen G, Hu Q, Li H . In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat Nanotechnol. 2018; 14(1):89-97. DOI: 10.1038/s41565-018-0319-4. View

12.

Huang C, Ye Z, Huang M, Lu J . Regulation of CD47 expression in cancer cells. Transl Oncol. 2020; 13(12):100862. PMC: 7494507. DOI: 10.1016/j.tranon.2020.100862. View

13.

Kruger S, Ilmer M, Kobold S, Cadilha B, Endres S, Ormanns S . Advances in cancer immunotherapy 2019 - latest trends. J Exp Clin Cancer Res. 2019; 38(1):268. PMC: 6585101. DOI: 10.1186/s13046-019-1266-0. View

14.

Chen X, Deng Y, Wang Z, Wei W, Zhou C, Zhang Y . Hypoxia-induced ZEB1 promotes cervical cancer progression via CCL8-dependent tumour-associated macrophage recruitment. Cell Death Dis. 2019; 10(7):508. PMC: 6602971. DOI: 10.1038/s41419-019-1748-1. View

15.

Chen X, Wei W, Wang Z, Wang N, Guo C, Zhou C . A novel lymphatic pattern promotes metastasis of cervical cancer in a hypoxic tumour-associated macrophage-dependent manner. Angiogenesis. 2021; 24(3):549-565. PMC: 8292274. DOI: 10.1007/s10456-020-09766-2. View

16.

Lequeux A, Noman M, Xiao M, Sauvage D, Van Moer K, Viry E . Impact of hypoxic tumor microenvironment and tumor cell plasticity on the expression of immune checkpoints. Cancer Lett. 2019; 458:13-20. DOI: 10.1016/j.canlet.2019.05.021. View

17.

de Miguel M, Calvo E . Clinical Challenges of Immune Checkpoint Inhibitors. Cancer Cell. 2020; 38(3):326-333. DOI: 10.1016/j.ccell.2020.07.004. View

18.

Brahimi-Horn M, Chiche J, Pouyssegur J . Hypoxia and cancer. J Mol Med (Berl). 2007; 85(12):1301-7. DOI: 10.1007/s00109-007-0281-3. View

19.

Matlung H, Szilagyi K, Barclay N, van den Berg T . The CD47-SIRPα signaling axis as an innate immune checkpoint in cancer. Immunol Rev. 2017; 276(1):145-164. DOI: 10.1111/imr.12527. View

20.

Feng M, Jiang W, Kim B, Zhang C, Fu Y, Weissman I . Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019; 19(10):568-586. PMC: 7002027. DOI: 10.1038/s41568-019-0183-z. View