Interferon-gamma signaling promotes melanoma progression and metastasis

Zhou, Bo; Basu, Jayati; Kazmi, Hasan Raza; Chitrala, Kumaraswamy Naidu; Mo, Xuan; Preston-Alp, Sarah; Cai, Kathy Q.; Kappes, Dietmar J.; Zaidi, M. Raza

doi:10.1038/s41388-022-02561-x

Cited by 6 publications

(5 citation statements)

References 64 publications

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“…Quantitative data were obtained for 3889 proteins with 253 proteins significantly changing in abundance by at least 2-fold between the IFN-γ and control condition (Figure 1B and Supplementary Table S2). Among the 76 proteins up-regulated, enrichments in genes involved in the "Immune system process", "Antigen processing and presentation", "Immune response" or "Response to interferon-gamma" were found (Figure 1C and Supplementary Figure S1) and were expected as they were known to be induced by IFN-γ from previous transcriptomics data from other melanoma cell lines [8]. When focusing on proteins down-regulated by IFN-γ, we found proteins involved in the cell cycle and cell division (Figure 1D and Supplementary Figure S2).…”

Section: Interferon-γ Reshapes the Proteome Of A375 Cells And Strongl...mentioning

confidence: 64%

“…were known to be induced by IFN-γ from previous transcriptomics data from other melanoma cell lines [8]. When focusing on proteins down-regulated by IFN-γ, we found proteins involved in the cell cycle and cell division (Figure 1D and Supplementary Figure S2).…”

Section: Interferon-γ Reshapes the Proteome Of A375 Cells And Strongl...mentioning

confidence: 79%

“…The 2 of 14 link between interferon-γ and melanoma is still not fully understood [7]. Indeed, IFN-γ signaling is frequently down-regulated in melanoma and seems important for the response to anti-CTLA4 and anti-PD1 therapies [3,4] but might play a dual role in melanoma or other types of cancers (pro-or anti-tumorigenic) [4,[7][8][9][10][11][12]. In addition, mutations of several genes involved in the response to IFN-γ in tumor cells render them resistant to certain therapies (e.g., anti-CTLA-4 therapy) [12].…”

Section: Introductionmentioning

confidence: 99%

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Tryptophanyl-Transfer RNA Synthetase Is Involved in a Negative Feedback Loop Mitigating Interferon-γ-Induced Gene Expression

Lazar,

Livneh,

Ciechanover

et al. 2024

Cells

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Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes responsible for linking a transfer RNA (tRNA) with its cognate amino acid present in all the kingdoms of life. Besides their aminoacyl-tRNA synthetase activity, it was described that many of these enzymes can carry out non-canonical functions. They were shown to be involved in important biological processes such as metabolism, immunity, development, angiogenesis and tumorigenesis. In the present work, we provide evidence that tryptophanyl-tRNA synthetase might be involved in a negative feedback loop mitigating the expression of certain interferon-γ-induced genes. Mining the available TCGA and Gtex data, we found that WARS was highly expressed in cutaneous melanoma (SKCM) compared to other cancers and is of good prognosis for this particular cancer type. WARS expression correlates with genes involved in antigen processing and presentation but also transcription factors involved in IFN-γ signaling such as STAT1. In addition, WARS was found in complex with STAT1 in A375 cells treated with IFN-γ. Finally, we showed that knocking down WARS expression during IFN-γ stimulation further increases the expression of GBP2, APOL1, ISG15, HLA-A and IDO1.

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Section: Interferon-γ Reshapes the Proteome Of A375 Cells And Strongl...mentioning

confidence: 64%

Section: Interferon-γ Reshapes the Proteome Of A375 Cells And Strongl...mentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Tryptophanyl-Transfer RNA Synthetase Is Involved in a Negative Feedback Loop Mitigating Interferon-γ-Induced Gene Expression

Lazar,

Livneh,

Ciechanover

et al. 2024

Cells

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“… 63 IFNγ pretreatment of melanoma cells prior to injection enhanced their tumorigenicity and increased the formation of lung metastasis in vivo further supporting increased resistance of melanoma cells to initial NK cell killing. 64 The inhibitory effect of MHC-I and IFNγ highlighted a crucial role of the NK cell response over T cells in the early phase of tumor cell elimination. Additional studies underlined the importance of NK cells during the early phase of tumor development and in the elimination of circulating metastases while the adaptive immune system, mostly cytotoxic T cells, was crucial to control already established tumor.…”

Section: Discussionmentioning

confidence: 99%

IFNγ mediates the resistance of tumor cells to distinct NK cell subsets

Hofman,

Ng,

Garcés-Lázaro

et al. 2024

J Immunother Cancer

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BackgroundImmune checkpoint blockade targeting the adaptive immune system has revolutionized the treatment of cancer. Despite impressive clinical benefits observed, patient subgroups remain non-responsive underscoring the necessity for combinational therapies harnessing additional immune cells. Natural killer (NK) cells are emerging tools for cancer therapy. However, only subpopulations of NK cells that are differentially controlled by inhibitory receptors exert reactivity against particular cancer types. How to leverage the complete anti-tumor potential of all NK cell subsets without favoring the emergence of NK cell-resistant tumor cells remains unresolved.MethodsWe performed a genome-wide CRISPR/Cas9 knockout resistance screen in melanoma cells in co-cultures with human primary NK cells. We comprehensively evaluated factors regulating tumor resistance and susceptibility by focusing on NK cell subsets in an allogenic setting. Moreover, we tested therapeutic blocking antibodies currently used in clinical trials.ResultsMelanoma cells deficient in antigen-presenting or the IFNγ-signaling pathways were depleted in remaining NK cell-co-cultured melanoma cells and displayed enhanced sensitivity to NK cells. Treatment with IFNγ induced potent resistance of melanoma cells to resting, IL-2-cultured and ADCC-activated NK cells that depended onB2Mrequired for the expression of both classical and non-classical MHC-I. IFNγ-induced expression of HLA-E mediated the resistance of melanoma cells to the NKG2A+KIR−and partially to the NKG2A+KIR+NK cell subset. The expression of classical MHC-I by itself was sufficient for the inhibition of the NKG2A−KIR+, but not the NKG2A+KIR+NK cell subset. Treatment of NK cells with monalizumab, an NKG2A blocking mAb, enhanced the reactivity of a corresponding subset of NK cells. The combination of monalizumab with lirilumab, blocking KIR2 receptors, together with DX9, blocking KIR3DL1, was required to restore cytotoxicity of all NK cell subsets against IFNγ-induced resistant tumor cells in melanoma and tumors of different origins.ConclusionOur data reveal that in the context of NK cells, IFNγ induces the resistance of tumor cells by the upregulation of classical and non-classical MHC-I. Moreover, we reveal insights into NK cell subset reactivity and propose a therapeutic strategy involving combinational monalizumab/lirilumab/DX9 treatment to fully restore the antitumor response across NK cell subsets.

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“…However, some patients with high IFN-gamma signature expression showed immune resistance, suggesting that an inflammatory microenvironment is necessary but not sufficient to achieve a response [ 37 ]. Tumoral intrinsic INF-gamma signaling has also shown in murine models an ambiguous pro-tumorigenic activity, contributing to melanoma progression by inhibiting cell apoptosis and enriching the tumor microenvironment of immunosuppressive polymorphonuclear leukocytes [ 42 ].…”

Section: First Line Predictive/prognostic Factorsmentioning

confidence: 99%

Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective

Poletto,

Paruzzo,

Nepote

et al. 2023

Cancers

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The introduction of immunotherapy revolutionized the treatment landscape in metastatic melanoma. Despite the impressive results associated with immune checkpoint inhibitors (ICIs), only a portion of patients obtain a response to this treatment. In this scenario, the research of predictive factors is fundamental to identify patients who may have a response and to exclude patients with a low possibility to respond. These factors can be host-associated, immune system activation-related, and tumor-related. Patient-related factors can vary from data obtained by medical history (performance status, age, sex, body mass index, concomitant medications, and comorbidities) to analysis of the gut microbiome from fecal samples. Tumor-related factors can reflect tumor burden (metastatic sites, lactate dehydrogenase, C-reactive protein, and circulating tumor DNA) or can derive from the analysis of tumor samples (driver mutations, tumor-infiltrating lymphocytes, and myeloid cells). Biomarkers evaluating the immune system activation, such as IFN-gamma gene expression profile and analysis of circulating immune cell subsets, have emerged in recent years as significantly correlated with response to ICIs. In this manuscript, we critically reviewed the most updated literature data on the landscape of predictive factors in metastatic melanoma treated with ICIs. We focus on the principal limits and potentiality of different methods, shedding light on the more promising biomarkers.

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Interferon-gamma signaling promotes melanoma progression and metastasis

Cited by 6 publications

References 64 publications

Tryptophanyl-Transfer RNA Synthetase Is Involved in a Negative Feedback Loop Mitigating Interferon-γ-Induced Gene Expression

Tryptophanyl-Transfer RNA Synthetase Is Involved in a Negative Feedback Loop Mitigating Interferon-γ-Induced Gene Expression

IFNγ mediates the resistance of tumor cells to distinct NK cell subsets

Predictive Factors in Metastatic Melanoma Treated with Immune Checkpoint Inhibitors: From Clinical Practice to Future Perspective

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