STAT3 inhibition reduces macrophage number and tumor growth in neurofibroma

Fletcher, Jonathan S.; Springer, Mitchell G.; Choi, Kwangmin; Jousma, Edwin; Rizvi, Tilat A.; Dombi, Eva; Kim, Miok; Wu, Jianqiang; Ratner, Nancy

doi:10.1038/s41388-018-0600-x

Cited by 46 publications

(40 citation statements)

References 38 publications

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“…Although there are not many studies toward application of FLLL32 in colon cancer, investigations regarding the roles of the p-STAT3 inhibitor on other types of cancers have been conducted by several researchers (Fletcher et al, 2019;Wang et al, 2016;Wu et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

STAT3 inhibition reduced PD‐L1 expression and enhanced antitumor immune responses

Jahangiri

Dadmanesh

Ghorban

2020

Journal Cellular Physiology

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Colon cancer is one the most common diagnosed cancers in America and Europe. Signal transducer and activator of transcription 3 (STAT3) in colon cancer is associated with proliferation of the tumor cells and suppression of immune responses. STAT3 activation upregulates the transcription of many suppressor genes, including programmed death‐ligand 1 (PD‐L1). This study was aimed to investigate the effect of STAT3 inhibition in a colon cancer cell line, HCT‐15, and particularly in presence of samples obtained from the patients suffering from colon cancer. In this project, the expression of PD‐L1 and apoptosis‐related proteins were assessed following STAT3 inhibition, using FLLL32, in HCT‐15 cells. To evaluate the effects of STAT3 inhibition on immune response, lymphocytes from 20 men with Stage III colon cancer and 20 healthy donors were cocultured with HCT‐15 cells in presence or absence of STAT3 inhibitor. Then, T regulatory (T‐reg) cell evaluation and intracellular cytokine staining (ICS) were performed using flowcytometry to assess the T‐reg and T helper (Th) subset cytokines following STAT3 inhibition. STAT3 inhibition suppressed PD‐L1 expression and induced apoptosis in HCT‐15 cells. The population of T‐reg cells in patients with colon cancer significantly decreased after treatment with STAT3 inhibitor. ICS revealed that STAT3 inhibition promotes Th1 protective immune responses. These findings suggest that STAT3 inhibition through either induction of apoptosis in the colon cancer cells and/or activation of efficient immune responses can lead to overcome cancer‐induced immune tolerance.

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Section: Discussionmentioning

confidence: 99%

STAT3 inhibition reduced PD‐L1 expression and enhanced antitumor immune responses

Jahangiri

Dadmanesh

Ghorban

2020

Journal Cellular Physiology

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“…5b). CCL2 has been proven to be targeted and regulated by STAT3 [30][31][32]. To confirm the role of CCL2 in TAM polarization, flow cytometry was performed to analyze the TAM markers in a co-culture system composed of LoVo-shCtrl/shCPEB3 or RKO-shCtrl/shCPEB3 cells, and TAMs.…”

Section: Cpeb3 Modulates Ccl2 Secretion In Crc Cell Supernatants To Rmentioning

confidence: 99%

CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling

Zhong

Fang

Lai

et al. 2020

J Exp Clin Cancer Res

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Background: Crosstalk between cancer cells and tumor-associated macrophages (TAMs) mediates tumor progression in colorectal cancer (CRC). Cytoplasmic polyadenylation element binding protein 3 (CPEB3) has been shown to exhibit tumor-suppressive role in CRC. Methods: The expression of CPEB3, CD68, CD86 and CD163 was determined in CRC tissues. SW480 or HCT116 cells overexpressing CPEB3 and LoVo or RKO cells with CPEB3 knockdown were constructed. Stably transfected CRC cells were co-cultured with THP-1 macrophages to determine the malignant phenotype of CRC cells, macrophage polarization, and secretory signals. The inhibition of CPEB3 on tumor progression and M2-like TAM polarization was confirmed in nude mice. Results: Decreased CPEB3 expression in CRC was associated with fewer CD86 + TAMs and more CD163 + TAMs. CPEB3 knockdown in CRC cells increased the number of CD163 + TAMs and the expression of IL1RA, IL-6, IL-4 and IL-10 in TAM supernatants. TAMs enhanced CRC cell proliferation and invasion via IL-6, and then activated the IL-6R/STAT3 pathway in CRC cells. However, CPEB3 reduced the IL-6R protein levels by directly binding to IL-6R mRNA, leading to decreased phosphorylated-STAT3 expression in CRC cells. CCL2 was significantly increased in CPEB3 knockdown cells, while CCL2 antibody treatment rescued the effect of CPEB3 knockdown in promoting CD163 + TAM polarization. Eventually, we confirmed that CPEB3 inhibits tumor progression and M2-like TAM polarization in vivo. Conclusions: CPEB3 is involved in the crosstalk between CRC cells and TAMs by targeting IL-6R/STAT3 signaling.

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“…Another target to repolarize macrophages is Janus kinase 2 (JAK2)/STAT3 pathways. STAT3 is activated in myeloid cells and promote tumor immunosuppression ( 191 ). The presence of TAMs upregulated the activation of STAT3 pathway in neuroblastoma tumor cells and administration of JAK/STAT inhibitor AZD1480 reduced TAM-mediated growth of neuroblastoma ( 67 ).…”

Section: Tam Targeted Immunotherapy In Neuroblastomamentioning

confidence: 99%

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

Liu

Joshi

2020

Front. Immunol.

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Neuroblastoma is the most common extracranial pediatric tumor and often presents with metastatic disease, and patients with high-risk neuroblastoma have survival rates of ~50%. Neuroblastoma tumorigenesis is associated with the infiltration of various types of immune cells, including myeloid derived suppressor cells, tumor associated macrophages (TAMs), and regulatory T cells, which foster tumor growth and harbor immunosuppressive functions. In particular, TAMs predict poor clinical outcomes in neuroblastoma, and among these immune cells, TAMs with an M2 phenotype comprise an immune cell population that promotes tumor metastasis, contributes to immunosuppression, and leads to failure of radiation or checkpoint inhibitor therapy. This review article summarizes the role of macrophages in tumor angiogenesis, metastasis, and immunosuppression in neuroblastoma and discusses the recent advances in “macrophage-targeting strategies” in neuroblastoma with a focus on three aspects: (1) inhibition of macrophage recruitment, (2) targeting macrophage survival, and (3) reprogramming of macrophages into an immunostimulatory phenotype.

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STAT3 inhibition reduces macrophage number and tumor growth in neurofibroma

Cited by 46 publications

References 38 publications

STAT3 inhibition reduced PD‐L1 expression and enhanced antitumor immune responses

STAT3 inhibition reduced PD‐L1 expression and enhanced antitumor immune responses

CPEB3 inhibits epithelial-mesenchymal transition by disrupting the crosstalk between colorectal cancer cells and tumor-associated macrophages via IL-6R/STAT3 signaling

“Re-educating” Tumor Associated Macrophages as a Novel Immunotherapy Strategy for Neuroblastoma

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