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PD-L1 expression increased by IFN-γ via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer.

ABSTRACT: PD-L1 inhibitors are widely used in tumor immunotherapy, but their mechanism in colorectal cancer remains unclear. The present study aimed to investigate the mechanisms underlying programmed death ligand 1 (PD-L1) regulation via the interferon-γ (IFN-γ)/janus kinase (JAK)/STAT signaling pathway, and its prognostic value in patients with colorectal cancer (CRC). A cohort of 181 patients were recruited to determine the association between PD-L1 expression and CRC prognosis; the patients were newly diagnosed with colorectal adenocarcinoma and had also undergone a physical tumorectomy. Immunohistochemical staining and survival analysis were used to evaluate the predictive value of PD-L1 protein expression in CRC. Gene set enrichment analysis, RT-qPCR and western blotting, etc were performed to confirm that PD-L1 is regulated by the IFN-γ/JAK/STAT signaling pathway. PD-L1 up-regulation was more frequently observed in patients with larger tumors, positive vascular or lymphatic infiltration and a poorly differentiated stage in addition to being associated with a poor survival in patients with CRC. Following the stimulation with IFN-γ, PD-L1 expression levels were revealed to be increased via the JAK2/STAT1 signaling pathway. In conclusion, the findings of the present study indicated that the expression levels of PD-L1 may be associated with a poor prognosis in patients with CRC. In addition, the results suggested that the IFN-γ-mediated overexpression of PD-L1 in CRC cells may be regulated by the JAK2/STAT1 signaling pathway.

SUBMITTER: Zhao T

PROVIDER: S-EPMC7377091 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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PD-L1 expression increased by IFN-γ via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer.

Zhao Tiancheng T Li Yezhou Y Zhang Jiayu J Zhang Bin B

Oncology letters 20200520 2

PD-L1 inhibitors are widely used in tumor immunotherapy, but their mechanism in colorectal cancer remains unclear. The present study aimed to investigate the mechanisms underlying programmed death ligand 1 (PD-L1) regulation via the interferon-γ (IFN-γ)/janus kinase (JAK)/STAT signaling pathway, and its prognostic value in patients with colorectal cancer (CRC). A cohort of 181 patients were recruited to determine the association between PD-L1 expression and CRC prognosis; the patients were newly ...[more]

PMID: 32724352

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Project description:BackgroundPD-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.MethodsThe 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.ResultsThe 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-γ level was positively correlated with PD-L1 expression in murine glioma. Further, IFN-γ induces PD-L1 expression on primary cultured microglia, bone marrow-derived macrophages, and GL261 glioma cells in vitro. Seven IFN-γ-induced genes, namely GBP5, ICAM1, CAMK2D, IRF1, SOCS3, CD44, and CCL2, were selected to calculate as substitute indicator for IFN-γ level. By combining the relative expression of the listed IFN-γ-induced genes, IFN-γ score was positively correlated with PD-L1 expression in different anatomic structures of human glioma and in glioma of different malignancies.ConclusionOur 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-γ is an important cause of PD-L1 expression in the glioma microenvironment. Further, we proposed IFN-γ score aggregated from the expressions of the listed IFN-γ-induced genes as a complementary prognostic indicator for anti-PD-1/PD-L1 therapy.

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.

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PD-L1 expression increased by IFN-γ via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer.

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PD-L1 expression increased by IFN-γ via JAK2-STAT1 signaling and predicts a poor survival in colorectal cancer.

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