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Modulation of IL-1? reprogrammes the tumor microenvironment to interrupt oral carcinogenesis.

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) development is a multistage process includes the normal, dysplasia and squamous cell carcinoma (SCC) stages. Recently, increasing evidence has suggested that the tumor microenvironment (TME) is an integral part of malignant transformation. Exploring certain key node genes in TME for future intervention in dysplasia to interrupt oral carcinogenesis was the primary goal of this research. To achieve this goal, systems biology approaches were first applied to the epithelia and fibroblasts collected at sequential stages in a 4-nitroquinoline-1-oxide (4NQO) -induced rat oral carcinogenesis model. Through bioinformatics network construction, IL-1? was identified as one of the key node genes in TME during carcinogenesis. Immunohistochemical staining of human and rat samples demonstrated that IL-1? expression patterns were parallel to the stages of malignant transformation. Silencing IL-1? with lentivirus-delivered shRNA significantly inhibited oral squamous cell carcinoma cell growth both in vivo and in vitro. Based on these findings, we hypothesized that IL-1? may be a chemoprevention target in TME during oral carcinogenesis. Therefore, we targeted IL-1 in the TME by oral mucosal injection of an IL-1 receptor antagonist in 4NQO rats. The results demonstrated that targeting IL-1 could interrupt oral carcinogenesis by reprogramming the TME.

SUBMITTER: Wu T

PROVIDER: S-EPMC4735323 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Modulation of IL-1β reprogrammes the tumor microenvironment to interrupt oral carcinogenesis.

Wu Tong T Hong Yun Y Jia Lihua L Wu Jie J Xia Juan J Wang Juan J Hu Qinchao Q Cheng Bin B

Scientific reports 20160201

Head and neck squamous cell carcinoma (HNSCC) development is a multistage process includes the normal, dysplasia and squamous cell carcinoma (SCC) stages. Recently, increasing evidence has suggested that the tumor microenvironment (TME) is an integral part of malignant transformation. Exploring certain key node genes in TME for future intervention in dysplasia to interrupt oral carcinogenesis was the primary goal of this research. To achieve this goal, systems biology approaches were first appli ...[more]

PMID: 26831400

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Project description:BackgroundChemoradiotherapy (CRT) remains one of the most common cancer treatment modalities, and recent data suggest that CRT is maximally effective when there is generation of an anti-tumoral immune response. However, CRT has also been shown to promote immunosuppressive mechanisms which must be blocked or reversed to maximize its immune stimulating effects.MethodsTherefore, using a preclinical model of human papillomavirus (HPV)-associated head and neck squamous cell carcinoma (HNSCC), we developed a clinically relevant therapy combining CRT and two existing immunomodulatory drugs: cyclophosphamide (CTX) and the small molecule inducible nitric oxide synthase (iNOS) inhibitor L-n6-(1-iminoethyl)-lysine (L-NIL). In this model, we treated the syngeneic HPV-HNSCC mEER tumor-bearing mice with fractionated (10 fractions of 3 Gy) tumor-directed radiation and weekly cisplatin administration. We compared the immune responses induced by CRT and those induced by combinatory treatment (CRT + CTX/L-NIL) with flow cytometry, quantitative multiplex immunofluorescence and by profiling immune-related gene expression changes.ResultsWe show that combination treatment favorably remodels the tumor myeloid immune microenvironment including an increase in anti-tumor immune cell types (inflammatory monocytes and M1-like macrophages) and a decrease in immunosuppressive granulocytic myeloid-derived suppressor cells (MDSCs). Intratumoral T cell infiltration and tumor antigen specificity of T cells were also improved, including a 31.8-fold increase in the CD8+ T cell/ regulatory T cell ratio and a significant increase in tumor antigen-specific CD8+ T cells compared to CRT alone. CTX/LNIL immunomodulation was also shown to significantly improve CRT efficacy, leading to rejection of 21% established tumors in a CD8-dependent manner.ConclusionsOverall, these data show that modulation of the tumor immune microenvironment with CTX/L-NIL enhances susceptibility of treatment-refractory tumors to CRT. The combination of tumor immune microenvironment modulation with CRT constitutes a translationally relevant approach to enhance CRT efficacy through enhanced immune activation.

Dataset Information

Modulation of IL-1? reprogrammes the tumor microenvironment to interrupt oral carcinogenesis.

Publications

Modulation of IL-1β reprogrammes the tumor microenvironment to interrupt oral carcinogenesis.

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