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The IFN-?/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy.

ABSTRACT: BACKGROUND:PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies. METHODS:The distribution of tumor-infiltrating T cells and PD-L1 expression was analyzed via immunofluorescence in orthotopic murine glioma model. The expression of PD-L1 in immune cell populations was detected by flow cytometry. Data excavated from TCGA LGG/GBM datasets and the Ivy Glioblastoma Atlas Project was used for in silico analysis of the correlation among genes and survival. RESULTS:The distribution of tumor-infiltrating T cells and PD-L1 expression, which parallels in murine orthotopic glioma model and human glioma microdissections, was interrelated. The IFN-? level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-? induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-?-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-? level. By combining the relative expression of the listed IFN-?-induced genes, IFN-? score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies. CONCLUSION:Our study identified the distribution of tumor-infiltrating T cells and PD-L1 expression in murine glioma model and human glioma samples. And we found that IFN-? is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-? score aggregated from the expressions of the listed IFN-?-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

SUBMITTER: Qian J

PROVIDER: S-EPMC6192101 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy.

Qian Jiawen J Wang Chen C Wang Bo B Yang Jiao J Wang Yuedi Y Luo Feifei F Xu Junying J Zhao Chujun C Liu Ronghua R Chu Yiwei Y

Journal of neuroinflammation 20181017 1

<h4>Background</h4>PD-L1 is an immune inhibitory receptor ligand that leads to T cell dysfunction and apoptosis by binding to its receptor PD-1, which works in braking inflammatory response and conspiring tumor immune evasion. However, in gliomas, the cause of PD-L1 expression in the tumor microenvironment is not yet clear. Besides, auxiliary biomarkers are urgently needed for screening possible responsive glioma patients for anti-PD-1/PD-L1 therapies.<h4>Methods</h4>The distribution of tumor-in ...[more]

PMID: 30333036

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Project description:BackgroundImmune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma.MethodsWe analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway.ResultsFor TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53L22Q,W23S, a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53L22Q,W23S in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression.ConclusionsWhile having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy.

Project description:BackgroundCircular RNAs (circRNAs) are a novel type of non-coding RNA, play an important role in the progression of tumors. However, the function and mechanism of circRNAs in regulating immune microenvironment of pancreatic cancer (PC) remain largely unclear.MethodsThe effects of hsa_circ_0046523 expression on proliferation, migration and invasion of PC cells were analyzed by CCK8 and Transwell assays. Flow cytometry was used to detect the proportion of CD4+ T cells, CD8+ T cells and Tregs in peripheral blood mononuclear cells (PBMCs) after co-culture, and the apoptosis, depletion and function of CD8+ T cells. The expression levels of immunoregulatory cytokines were detected by enzyme linked immunosorbent assay (ELISA). The dual-luciferase reporter was performed to determine the interaction between hsa_circ_0046523, miR-148a-3p, and PD-L1. Rescue experiments and PD-L1 blocking experiments were employed to investigate whether hsa_circ_0046523 exerts its biological function by miR-148a-3p/PD-L1 in PC. Furthermore, an immunocompetent murine PC model was established to confirm these findings.ResultsHsa_circ_0046523 expression was remarkably upregulated in PC tissues and cell lines. Moreover, high expression of hsa_circ_0046523 was correlated with advanced pathological stage and poorer prognosis. Hsa_circ_0046523 overexpression promoted the proliferation, migration and invasion of PC cells in vitro. Co-culture experiments confirmed that forced expression of hsa_circ_0046523 could decrease the proportion of CD4+ and CD8+ T cells, as well as increase the proportion of Tregs among peripheral blood mononuclear cells (PBMCs). Meanwhile, hsa_circ_0046523 overexpression promoted the apoptosis and exhaustion of CD8+ T cells, inhibited CD8+ T cell function, increased the secretion of immunosuppressive cytokines IL-10 and TGF-β, and decreased the secretion of immune effector cytokines IFN-γ and IL-2 among PBMCs. Mechanistically, hsa_circ_0046523 exerted its biological function by binding to miR-148a-3p to upregulate PD-L1 expression in PC. Moreover, these immune modulating functions of miR-148a-3p/PD-L1 axis were also confirmed in an immunocompetent murine PC model.ConclusionsOur study suggests that hsa_circ_0046523/miR-148a-3p/PD-L1 regulatory axis mediates PC immunosuppressive microenvironment and these molecules are expected to be new targets for remodeling tumor immune microenvironment of PC.

Dataset Information

The IFN-?/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy.

Publications

The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy.

Similar Datasets

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