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Reprogramming of tumor-associated macrophages by targeting ?-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer.

ABSTRACT: Tumor-associated macrophages (TAMs) influence lung tumor development by inducing immunosuppression. Transcriptome analysis of TAMs isolated from human lung tumor tissues revealed an up-regulation of the Wnt/?-catenin pathway. These findings were reproduced in a newly developed in vitro “trained” TAM model. Pharmacological and macrophage-specific genetic ablation of ?-catenin reprogrammed M2-like TAMs to M1-like TAMs both in vitro and in various in vivo models, which was linked with the suppression of primary and metastatic lung tumor growth. An in-depth analysis of the underlying signaling events revealed that ?-catenin–mediated transcriptional activation of FOS-like antigen 2 (FOSL2) and repression of the AT-rich interaction domain 5A (ARID5A) drive gene regulatory switch from M1-like TAMs to M2-like TAMs. Moreover, we found that high expressions of ?-catenin and FOSL2 correlated with poor prognosis in patients with lung cancer. In conclusion, ?-catenin drives a transcriptional switch in the lung tumor microenvironment, thereby promoting tumor progression and metastasis.

SUBMITTER: Sarode P

PROVIDER: S-EPMC7274802 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Project description:Background: Tumor associated macrophages (TAMs) have strong plasticity and if reprogrammed, can clear tumor cells and regulate the adaptive immune system for cancer immunotherapy. Deubiquitinating enzymes (DUBs), which can remove ubiquitin (Ub) from Ub-modified substrates, have been associated with oncogenic metabolism but are not well-known for regulating TAMs repolarization. Methods: The expression of DUB related genes in macrophages (M?s) was detected by reverse transcription-PCR. Flow cytometry and immunofluorescence were used to detect the changes of immune cells in the tumor microenvironment and spleen, including M1 (CD11b+F4/80+CD86+CD206-), and M2 (CD11b+F4/80+CD86-CD206+) M?s, and IFN-?+CD8+T cells. A proliferation assay was used to determine the effect of M2 M?s treated with a USP7 inhibitor on T cell proliferation. Western blotting was used to detect the expression of USP7 and the activation of the MAPK pathway. The TGCA database was used to assess the role of USP7 in the immune microenvironment of human lung adenocarcinoma (LUAD). Results: 51 DUB genes were screened and USP7 was identified as a highly expressed gene in M2 but not M1 M?s. Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 M?s, favoring CD8+T cells proliferation in vitro. USP7 inhibitors delayed tumor growth in mice with Lewis lung carcinoma, and promoted tumor infiltration of M1 M?s and IFN-?+CD8+T cells. Depletion of TAMs attenuated these therapeutic effects. USP7 inhibition was shown to mediate M?s reprogramming by activating the p38 MAPK pathway. Administration of USP7 inhibitors increased the expression of programmed cell death ligand 1 (PD-L1) in tumors, while blocking programmed cell death protein 1 (PD-1) provided an effective anti-tumor response. Clinical databases suggest that high expression of USP7 in LUAD was negatively correlated with innate and adaptive immunity. Conclusions: Taken together, these results provide evidence to suggest that therapeutic approaches targeting USP7, in combination with immunotherapy, should be considered for lung cancer treatment.

Project description:BackgroundTumour-associated macrophages (TAMs) in the tumour microenvironment (TME) can promote the progression of hepatocellular carcinoma (HCC). Some tumours can be suppressed by targeting Wnt2b in tumour cells. However, the role of Wnt2b in HCC is still unknown. In particular, the role of Wnt2b-mediated signal activation in macrophage polarization in the HCC microenvironment, and the regulatory effect between Wnt and glycolysis in TAMs has not been described.MethodsThe expression of Wnt2b in TAMs was detected by qPCR and immunofluorescence. Wnt2b/β-catenin interference in HCC-TAMs was performed by lentivirus carrying targeted shRNA or TLR9 agonist. Markers related to macrophage polarization and the changes of key glycolytic enzymes expression were detected by flow cytometry and qPCR. ECAR was analysed by Seahorse analyser. MTT assay, wound healing assay, western blotting were used to evaluate the promoting effect of different HCC-TAMs on the proliferation, migration and EMT of HCC in vitro. Tumour cells and different HCC-TAMs were injected via subcutaneously into immunodeficient mice to assess the effects of CpG ODN, Wnt2b, or β-catenin on HCC-TAMs in tumour growth in vivo.ResultsPolarization-promoting factors derived from HCC cells upregulated the expression of Wnt2b in macrophages, which promoted the polarization of TAMs to M2-like macrophages by activating Wnt2b/β-catenin/c-Myc signalling. Furthermore, this process was associated with the activation of glycolysis in HCC-TAMs. These HCC-TAMs could promote the development of EMT, proliferation, and migration of HCC. In addition to silencing Wnt2b or β-catenin expression, TLR9 agonist CpG ODN downregulated the level of glycolysis and inhibited the M2 polarization of HCC-TAMs, reversing the tumour-promoting effects of TAMs in vitro and vivo.ConclusionsAs a potential target for HCC therapy, Wnt2b may play an important regulatory role for the functions of TAMs in the TME. Moreover, the TLR9 agonist CpG ODN might act as a Wnt2b signal inhibitor and can potentially be employed for HCC therapy by disturbing Wnt2b/β-catenin/c-Myc and inhibiting glycolysis in HCC-TAMs.

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Reprogramming of tumor-associated macrophages by targeting ?-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer.

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