Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma

Bu, Lin‐Lin; Yu, Guang‐Tao; Deng, Wei‐Wei; Mao, Liang; Liu, Jianfeng; Ma, Si‐Rui; Fan, Teng-Fei; Hall, Bradford; Kulkarni, Ashok B.; Zhang, Wenfeng; Sun, Zhi‐Jun

doi:10.1080/2162402x.2015.1130206

Cited by 34 publications

(31 citation statements)

References 81 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our remarkable results in this study indicate that Notch1 inhibition can reduce the population of MDSCs in the tumour microenvironment. Moreover, our previous studies showed that DAPT decrease the phosphorylation of signal transducer and activator of transcription 3 (STAT3), which plays an important role in myeloid cell expansion and inhibition of maturation . Nonetheless, due to certain limitations of our studies, more investigations are required to confirm the mechanisms of how Notch1 signaling regulates MDSCs in HNSCC.…”

Section: Discussionmentioning

confidence: 90%

“…The Western blot analysis was performed according to our previously described procedures. 27 Briefly, tumours were carefully dissected from Tgfbr1/Pten 2cKO mice and lysed in a T-PER buffer containing 1% phosphatase inhibitors and complete mini cocktail (Roche). About 40 lg of protein from each sample was denatured and then loaded in each lane of NuPAGE 4-12% Bis-Tris precast gel.…”

Section: Western Blotmentioning

confidence: 99%

See 1 more Smart Citation

γ‐Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma

Mao

Zhao

et al. 2017

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

Immune evasion is a hallmark feature of cancer, and it plays an important role in tumour initiation and progression. In addition, tumour immune evasion severely hampers the desired antitumour effect in multiple cancers. In this study, we aimed to investigate the role of the Notch pathway in immune evasion in the head and neck squamous cell carcinoma (HNSCC) microenvironment. We first demonstrated that Notch1 signaling was activated in a Tgfbr1/Pten-knockout HNSCC mouse model. Notch signaling inhibition using a γ-secretase inhibitor (GSI-IX, DAPT) decreased tumour burden in the mouse model after prophylactic treatment. In addition, flow cytometry analysis indicated that Notch signaling inhibition reduced the sub-population of myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and regulatory T cells (Tregs), as well as immune checkpoint molecules (PD1, CTLA4, TIM3 and LAG3), in the circulation and in the tumour. Immunohistochemistry (IHC) of human HNSCC tissues demonstrated that elevation of the Notch1 downstream target HES1 was correlated with MDSC, TAM and Treg markers and with immune checkpoint molecules. These results suggest that modulating the Notch signaling pathway may decrease MDSCs, TAMs, Tregs and immune checkpoint molecules in HNSCC.

show abstract

Section: Discussionmentioning

confidence: 90%

Section: Western Blotmentioning

confidence: 99%

γ‐Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma

Mao

Zhao

et al. 2017

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

show abstract

“…Additionally, our previous study revealed that the population of CD8 + T cells was significantly decreased during the tumorigenesis and tumor progression in the 2cKO mice [29, 38]. This prompted us to investigate the expression of A2AR in the CD8 + T cells in the 2cKO tumor bearing mice.…”

Section: Resultsmentioning

confidence: 99%

Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma

et al. 2017

Self Cite

View full text Add to dashboard Cite

BackgroundCancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC.MethodsThe expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues. The immunotherapeutic value of A2AR blockade was assessed in vivo in genetically defined immunocompetent HNSCC mouse model.ResultsImmunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status. Elevated A2AR expression was also detected in recurrent HNSCC and HNSCC tissues with induction chemotherapy. The expression of A2AR was found to be significantly correlated with HIF-1α, CD73, CD8 and Foxp3. Furthermore, the increased population of CD4+Foxp3+ regulatory T cells (Tregs), which partially expressed A2AR, was observed in an immunocompetent mouse model that spontaneously develops HNSCC. Pharmacological blockade of A2AR by SCH58261 delayed the tumor growth in the HNSCC mouse model. Meanwhile, A2AR blockade significantly reduced the population of CD4+ Foxp3+ Tregs and enhanced the anti-tumor response of CD8+ T cells.ConclusionsThese results offer a preclinical proof for the administration of A2AR inhibitor on prophylactic experimental therapy of HNSCC and suggest that A2AR blockade can be a potential novel strategy for HNSCC immunotherapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s12943-017-0665-0) contains supplementary material, which is available to authorized users.

show abstract

“…32 And our previous study indicated that targeting STAT3 can reduce immunosuppressive myeloid cells in HNSCC. 33 In several cancers, STAT3 serves as a downstream target of SFKs. …”

Section: Effect Of Dasatinib On Immune Suppression Of Mouse Modelmentioning

confidence: 99%

Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

Mao

Deng

et al. 2016

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI 1 SRT 1 )was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy.

show abstract

Targeting STAT3 signaling reduces immunosuppressive myeloid cells in head and neck squamous cell carcinoma

Cited by 34 publications

References 81 publications

γ‐Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma

γ‐Secretase inhibitor reduces immunosuppressive cells and enhances tumour immunity in head and neck squamous cell carcinoma

Blockade of adenosine A2A receptor enhances CD8+ T cells response and decreases regulatory T cells in head and neck squamous cell carcinoma

Inhibition of SRC family kinases reduces myeloid‐derived suppressor cells in head and neck cancer

Contact Info

Product

Resources

About