Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma

Smithy, James W.; Moore, Lauren M.; Pelekanou, Vassiliki; Rehman, Jamaal; Gaule, Patricia; Wong, Pok Fai; Neumeister, Veronique; Sznol, Mario; Kluger, Harriet M.; Rimm, David L.

doi:10.1186/s40425-017-0229-2

Cited by 38 publications

(32 citation statements)

References 37 publications

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“…Therefore, to assess the relationship between these markers, we used Pearson correlation coefficient. As expected, CD274 (PD-L1) correlated with all three genes, including PDCD1LG2 (PD-L2) , CD8A and IRF1, which is consistent with the upregulation of IFNγ pathway reported in previous literature [10, 26, 30, 31].…”

Section: Discussionsupporting

confidence: 92%

Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma

Gupta¹,

McCann²,

Chan³

et al. 2019

j. immunotherapy cancer

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BackgroundIn melanoma, there is no companion diagnostic test to predict response to programmed cell death 1 (PD-1) axis immune checkpoint inhibitor (ICI) therapy. In the adjuvant setting, only one in five patients may benefit from ICI, so a biomarker is needed to select those that may or may not benefit. Here, we test a new 4-gene multiplex immunotherapy panel with research use only (RUO) prototype mRNA expression profile on the GeneXpert closed system using real-time quantitative reverse transcription polymerase chain reaction (RT-qPCR) for association with clinical benefit after treatment with ICI therapy in metastatic melanoma patients.MethodsPretreatment formalin-fixed paraffin-embedded (FFPE) tissue sections from melanoma patients treated with anti-PD-1 therapy (pembrolizumab, nivolumab, or ipilimumab plus nivolumab) between 2011 and 17 were selected from the Yale Pathology archives. FFPE sections were macrodissected to enrich for tumor for quantitative assessment of CD274 (PD-L1), PDCD1LG2 (PD-L2), CD8A, and IRF1 by RT-qPCR multiplex mRNA panel. Multiplex panel transcript levels were correlated with clinical benefit (complete response [CR], partial response [PR], stable disease [SD]); disease outcomes (progression-free survival [PFS] and overall survival [OS]); and protein levels assessed by quantitative immunofluorescence (QIF).ResultsTranscript levels were significantly higher in responders (CR/PR/SD) than in nonresponders (PD) for CD8A (p = 0.0001) and IRF1 (p = 0.0019). PFS was strongly associated with high CD274 (p = 0.0046), PDCD1LG2 (p = 0.0039), CD8A (p = 0.0002), and IRF1 (p = 0.0030) mRNA expression. Similar associations were observed for OS with high CD274 (p = 0.0004), CD8A (p = 0.0030), and IRF1 (p = 0.0096) mRNA expression. Multivariate analyses revealed significant PFS and OS associations with immunotherapy panel markers independent of baseline variables. Exploratory analyses revealed a novel significant association of high combined CD274 & PDCD1LG2 (L1/L2) transcript expression with PFS (p < 0.0001) and OS (p = 0.0011), which remained significant at a multivariate level for both PFS (HR = 0.31) and OS (HR = 0.39).ConclusionsIndividual immunotherapy panel markers CD274, PDCD1LG2, CD8A, IRF1 and a combined L1/L2 mRNA levels show promising associations with melanoma immunotherapy outcome. The turnaround time of the test (2 h) and easy standardization of the platform makes this an attractive approach for further study in the search for predictive biomarkers for ICI.

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Section: Discussionsupporting

confidence: 92%

Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma

Gupta¹,

McCann²,

Chan³

et al. 2019

j. immunotherapy cancer

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“…Although it is still not clear whether incomplete IFNγ stimulation in melanoma cells has significant impact on patient responses to immunotherapy, it is evident that this pathway is important for response to PD-1 blockade. In particular, nuclear expression of the IFNγ transcription factor IRF1 ( 25 ) is associated with better response to anti-PD-1 therapy in melanoma ( 26 ) and loss-of-function mutations in IFNγ pathway modulators (JAK1, JAK2) are associated with resistance to anti-PD-1 treatment. Moreover, murine B16 melanoma cells deficient in JAK1 or IFNGR1 grew faster than control B16 cells in response to immune therapy ( 27 ).…”

Section: Discussionmentioning

confidence: 99%

Interferon Signaling Is Frequently Downregulated in Melanoma

et al. 2018

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Immune checkpoint inhibitors that block the programmed cell death protein 1/PD-L1 pathway have significantly improved the survival of patients with advanced melanoma. Immunotherapies are only effective in 15–40% of melanoma patients and resistance is associated with defects in antigen presentation and interferon signaling pathways. In this study, we examined interferon-γ (IFNγ) responses in a large panel of immune checkpoint inhibitor-naïve melanoma cells with defined genetic drivers; BRAF-mutant (n = 11), NRAS-mutant (n = 10), BRAF/NRAS wild type (n = 10), and GNAQ/GNA11-mutant uveal melanomas (UVMs) (n = 8). Cell surface expression of established IFNγ downstream targets PD-L1, PD-L2, HLA-A, -B, and -C, HLA-DR, and nerve growth factor receptor (NGFR) were analyzed by flow cytometry. Basal cellular expression levels of HLA-A, -B, -C, HLA-DR, NGFR, and PD-L2 predicted the levels of IFNγ-stimulation, whereas PD-L1 induction was independent of basal expression levels. Only 13/39 (33%) of the melanoma cell lines tested responded to IFNγ with potent induction of all targets, indicating that downregulation of IFNγ signaling is common in melanoma. In addition, we identified two well-recognized mechanisms of immunotherapy resistance, the loss of β-2-microglobulin and interferon gamma receptor 1 expression. We also examined the influence of melanoma driver oncogenes on IFNγ signaling and our data suggest that UVM have diminished capacity to respond to IFNγ, with lower induced expression of several targets, consistent with the disappointing response of UVM to immunotherapies. Our results demonstrate that melanoma responses to IFNγ are heterogeneous, frequently downregulated in immune checkpoint inhibitor-naïve melanoma and potentially predictive of response to immunotherapy.

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“…IFNs play an important role in the regulation of antigen processing and presentation and are described to exert pro-and anti-tumorigenic effects in various types of cancer as extensively reviewed by Musella et al and Castro et al [91,92]. Downregulation of both type I and II IFN-mediated pathways have been described as mechanisms involved in resistance to CPI-and adoptive cell therapy in melanoma and lung cancer, indicating the potential of interference in these pathways to increase anti-tumor immunity [4][5][6]10,[93][94][95][96]. Several factors affecting IFN pathway expression have been described, revealing potential targets to modulate MHC-I expression in cancer.…”

Section: Inducing Mhc-i Expression In Cancer Via Restored Ifn Signalingmentioning

confidence: 99%

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

Cornel

Mimpen

Nierkens

2020

Cancers

260

203

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In recent years, major advances have been made in cancer immunotherapy. This has led to significant improvement in prognosis of cancer patients, especially in the hematological setting. Nonetheless, translation of these successes to solid tumors was found difficult. One major mechanism through which solid tumors can avoid anti-tumor immunity is the downregulation of major histocompatibility complex class I (MHC-I), which causes reduced recognition by- and cytotoxicity of CD8+ T-cells. Downregulation of MHC-I has been described in 40–90% of human tumors, often correlating with worse prognosis. Epigenetic and (post-)transcriptional dysregulations relevant in the stabilization of NFkB, IRFs, and NLRC5 are often responsible for MHC-I downregulation in cancer. The intrinsic reversible nature of these dysregulations provides an opportunity to restore MHC-I expression and facilitate adaptive anti-tumor immunity. In this review, we provide an overview of the mechanisms underlying reversible MHC-I downregulation and describe potential strategies to counteract this reduction in MHC-I antigen presentation in cancer.

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Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma

Cited by 38 publications

References 37 publications

Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma

Closed system RT-qPCR as a potential companion diagnostic test for immunotherapy outcome in metastatic melanoma

Interferon Signaling Is Frequently Downregulated in Melanoma

MHC Class I Downregulation in Cancer: Underlying Mechanisms and Potential Targets for Cancer Immunotherapy

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