IRF-1 responsiveness to IFN-γ predicts different cancer immune phenotypes

Murtas, Daniela; Maric, Dragan; Giorgi, De; Reinboth, Jennifer; Worschech, Andrea; Fetsch, Patricia; Filie, Armando C.; Ascierto, Ml; Bedognetti, Davide; Liu, Q; Uccellini, Lorenzo; Chouchane, Lotfi; Wang, E; Marincola, F.M.; Tomei, Sara

doi:10.1038/bjc.2013.335

Cited by 58 publications

(42 citation statements)

References 31 publications

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“…A recent study using cell lines shows a strong correlation between basal status of IRF‐1 activation and its IFN‐γ‐induced activation. Moreover, IRF‐1 responsiveness to IFN‐γ indicates the different intrinsic properties of cancer cells . Significantly increased expression of IRF‐1 was observed in tumor tissues from the IFN‐γ + PD‐L1 + group compared to other groups (Fig.…”

Section: Resultsmentioning

confidence: 92%

IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

Gao

Yang

Cai

et al. 2018

Intl Journal of Cancer

171

127

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IFN-γ plays a crucial role in anti-tumor responses and also induces expression of PD-L1, a well-established inhibitor of anti-tumor immune function. Understanding how molecular signaling regulates the function of IFN-γ might improve its anti-tumor efficacy. Here, we show that the tumor expression of IFN-γ expression alone has no significant prognostic value in patients with locally advanced lung adenocarcinoma. Surprisingly, patients with tumors expressing both IFN-γ and PD-L1 have the best prognosis compared to those with tumors expressing IFN-γ or PD-L1 alone. Transcriptome analysis demonstrated that tumor tissues expressing IFN-γ display gene expression associated with suppressed cell cycle progression and expansion. Unexpectedly this profile was observed in PD-L1 but not PD-L1- tumors. The current concept is that PD-L1 functions as a shield protecting tumor cells from cytolytic T cell (CTL)-mediated anti-tumor progression. However, our data indicate that PD-L1 expression in the presence of IFN-γ might serve as biomarker for the sensitivity of tumors to the inhibitory effect of IFN-γ. Mechanistic analysis revealed that in lung adenocarcinoma cells IFN-γ-induced activation of JAK2-STAT1 and PI3K-AKT pathways. The activation of JAK2-STAT1 is responsible for the anti-proliferative effect of IFN-γ. Inhibition of PI3K downregulated PD-L1 expression and enhanced the anti-proliferative effect of IFN-γ, suggesting that blockade of PI3K might maximize the IFN-γ-mediated anti-tumor effect. Our findings provide evidence for crosstalk between JAK2-STAT1 and PI3K-AKT pathways in response to IFN-γ in lung adenocarcinoma and have implications for the design of combinatorial targeted therapy and immunotherapy for the treatment of lung adenocarcinoma.

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Section: Resultsmentioning

confidence: 92%

IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

Gao

Yang

Cai

et al. 2018

Intl Journal of Cancer

171

127

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“…The signature also includes S100A9 and 4 related genes ( S100A7, S100A8, S100A12 , and PI3 ), which participate in a cell signaling response to tissue damage 15. Eight immune group genes ( CCL5, CD38, CXCL10, CXCL9, IRF1, LCP2, PTPRC , and SELL ) are also included and appear to function in tumor immune response signaling 16, 17, 18, 19, 20. Both of these gene groups were selected on the basis of differential expression in benign nevi and malignant melanoma, with increased expression in melanoma.…”

Section: Methodsmentioning

confidence: 99%

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi

Clarke

Flake

Busam

et al. 2016

Cancer

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BACKGROUNDRecently, a 23‐gene signature was developed to produce a melanoma diagnostic score capable of differentiating malignant and benign melanocytic lesions. The primary objective of this study was to independently assess the ability of the gene signature to differentiate melanoma from benign nevi in clinically relevant lesions.METHODSA set of 1400 melanocytic lesions was selected from samples prospectively submitted for gene expression testing at a clinical laboratory. Each sample was tested and subjected to an independent histopathologic evaluation by 3 experienced dermatopathologists. A primary diagnosis (benign or malignant) was assigned to each sample, and diagnostic concordance among the 3 dermatopathologists was required for inclusion in analyses. The sensitivity and specificity of the score in differentiating benign and malignant melanocytic lesions were calculated to assess the association between the score and the pathologic diagnosis.RESULTSThe gene expression signature differentiated benign nevi from malignant melanoma with a sensitivity of 91.5% and a specificity of 92.5%.CONCLUSIONSThese results reflect the performance of the gene signature in a diverse array of samples encountered in routine clinical practice. Cancer 2017;123:617–628. © 2016 American Cancer Society.

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“…These tumors are characterized by the activation of specific molecular pathways that are also found in other forms of immune-mediated rejection, such as allograft rejection or flares of autoimmunity [66,67]. We refer to them as the Immunologic Constant of Rejection (ICR) [2,68,69,70,71]. These pathways comprise the IFN-stimulated gene pathway (centered on IRF1 and STAT1), CXCR3 and CCR5 ligand pathways (e.g., CXCL9-11 and CCL3-5), and immune effector function genes (e.g., perforin, granulysin) [2,69].…”

Section: Pd-l1 Expression In Breast Cancer and Clinical Relevancementioning

confidence: 99%

Checkpoint Inhibitors and Their Application in Breast Cancer

et al. 2016

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Immune checkpoints are crucial for the maintenance of self-tolerance and for the modulation of immune responses in order to minimize tissue damage. Tumor cells take advantage of these mechanisms to evade immune recognition. A significant proportion of tumors, including breast cancers, can express co-inhibitory molecules that are important formediating the escape from T cell-mediated immune surveillance. The interaction of inhibitory receptors with their ligands can be blocked by specific molecules. Monoclonal antibodies (mAbs) directed against the cytotoxic T lymphocyte-associated antigen-4 (CTLA4) and, more recently, against the programmed cell death protein 1 (PD1), have been approved for the therapy of melanoma (anti-CTLA4 and anti-PD1 mAbs) and non-small cell lung cancer (anti-PD1 mAbs). Moreover, inhibition of PD1 signaling has shown extremely promising signs of activity in breast cancer. An increasing number of molecules directed against other immune checkpoints are currently under clinical development. In this review, we summarize the evidence supporting the implementation of checkpoint inhibition in breast cancer by reviewing in detail data on PD-L1 expression and its regulation. In addition, opportunities to boost anti-tumor immunity in breast cancer with checkpoint inhibitor-based immunotherapies alone and in combination with other treatment options will be discussed.

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IRF-1 responsiveness to IFN-γ predicts different cancer immune phenotypes

Cited by 58 publications

References 31 publications

IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

IFN‐γ‐mediated inhibition of lung cancer correlates with PD‐L1 expression and is regulated by PI3K‐AKT signaling

An independent validation of a gene expression signature to differentiate malignant melanoma from benign melanocytic nevi

Checkpoint Inhibitors and Their Application in Breast Cancer

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