Conserved interferon-gamma signaling and decreased immune exclusion programs in responses to immune checkpoint blockade therapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE154996 | GEO | 2020/07/24
REPOSITORIES: GEO
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Project description:We analyzed baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). Analysis of whole transcriptome data showed that T cell infiltration and interferon-gamma signaling signatures corresponded most highly with clinical response to therapy, with a reciprocal decrease in cell cycle and WNT signaling pathways in responding biopsies. Clinical outcome differences were likely not due to differential melanoma cell responses to interferon-gamma, as 57 human melanoma cell lines exposed in vitro to this cytokine showed a conserved interferon-gamma transcriptome response unless they had mutations that precluded signaling from the interferon-gamma receptor. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream interferon-gamma signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
| EGAS00001004545 | EGA
Project description:Immune checkpoint inhibitors (ICIs) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. Interferon-gamma (IFNg) signaling and the expression of IFNg-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNg-inducible immunostimulatory genes are required for response to ICIs, chronic IFNg signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of ULK1 correlate with poor survival in melanoma patients and overexpression of ULK1 in melanoma cells enhances IFNg-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacological inhibition of ULK1 reduces expression of IFNg-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the PD-L1 promoter region. Additionally, pharmacological inhibition of ULK1 in combination with anti-PD-1 therapy further reduces melanoma tumor growth and enhances anti-tumor immune responses in vivo. Our data suggest that targeting ULK1 represses IFNg-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of melanoma patients to improve response rates and patient outcomes.
2023-02-02 | PXD035347 | Pride
Project description:Background:Acral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. Methods: We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. Results: 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3 + CD8 + PD1 + intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low vs high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared to responders across cancers, including acral melanoma, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. Conclusions: A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.
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Project description:Indoleamine 2, 3-dioxygenase 1 (IDO1) is a metabolic enzyme catalyzing the conversion of the essential amino acid tryptophan to kynurenine. It is induced by IFNg and its expression is linked to poor prognosis across various cancer types. T cells are particularly sensitive to IDO1-dependent tryptophan deprivation in the tumor microenvironment, leading to tumor immune resistance. Therefore, IDO1 inhibitors, such as epacadostat, have been developed, aiming to restore T cell antitumor activity. However, a recent phase III trial assessing the clinical benefit of epacadostat with the PD-1 antibody pembrolizumab in melanoma failed. This prompted us to study the role of IDO1, and the effect of its inhibition, on tumor cells that are under IFNg treatment and T cell attack. We showed that IDO1-mediated tryptophan depletion contributes to the anti-tumor effect of CD8 T cells. Thus, while epacadostat expectedly replenished tryptophan -the desired effect-, this led to adverse protection of melanoma cells from T cell-derived IFNg. RNA sequencing and ribosome profiling of (patient-derived) melanoma cell lines revealed that IFNg caused general protein translation shut down, which was reversed by IDO1 inhibition. Impaired translation was accompanied by an amino acid deprivation-dependent stress response driving ATF4high and MITFlow transcriptomic signatures, which was also observed in melanoma patient tumors. Downregulation of MITF in tumors and PDX- derived cell lines upon treatment was strongly predictive of response to response, to checkpoint blockade-treatment and IFNg, respectively. Conversely, MITF restoration in cultured tumor cells caused T cell resistance. These results highlight the critical role of tryptophan in the melanoma response to T cell-derived IFNg, uncovering an unexpected negative consequence of IDO1 inhibition.
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Project description:Interferon-gamma (IFNg) exerts potent growth inhibitory (antiproliferative/pro-apoptotic) effects on a wide range of tumors, including melanoma. While several terminal effectors of cell cycle arrest and apoptosis have been identified, a definitive account of the signaling pathway leading to these events is lacking. We set up a chemical genomics screen and a whole genome targeting CRISPR/Cas9 screen in a growth inhibition (GI)-sensitive patient-derived melanoma (PDM) cell line. Drug screening revealed that treatment with RAF and ERK inhibitors disrupted IFNg GI in PDM cells. For the CRISPR screen, the gene-level analysis showed that the magnitude of enrichment for guide RNAs targeting ERK2 in IFNg-treated cells was comparable to core IFNg signaling proteins like IFNGR2, JAK1, JAK2, and STAT1. We validated the involvement of ERK by detecting a sustained increase in phospho-ERK1/2 (p-ERK) levels following IFNg treatment. In live imaging experiments, we found that an ERK inhibitor (ERKi) blocks the induction of cell death in 17 of 23 (~74%) IFNg-sensitive PDM lines covering all the MAPK mutant and triple wildtype molecular subtypes. Through gene expression analysis, we found that IFNg-ERK signaling triggered the expression of stress response genes and subsequent upregulation of DR5 and NOXA, which were both critical for the induction of cell death. In summary, the IFNg-ERK signaling axis mediates cell death downstream of IFNg treatment in melanoma cells. Our results provide a new understanding of the IFNg-mediated GI pathway that will also be crucial to define mechanisms of GI resistance in tumor cells.
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Project description:Interferon-gamma (IFNg) exerts potent growth inhibitory (antiproliferative/pro-apoptotic) effects on a wide range of tumors, including melanoma. While several terminal effectors of cell cycle arrest and apoptosis have been identified, a definitive account of the signaling pathway leading to these events is lacking. We set up a chemical genomics screen and a whole genome targeting CRISPR/Cas9 screen in a growth inhibition (GI)-sensitive patient-derived melanoma (PDM) cell line. Drug screening revealed that treatment with RAF and ERK inhibitors disrupted IFNg GI in PDM cells. For the CRISPR screen, the gene-level analysis showed that the magnitude of enrichment for guide RNAs targeting ERK2 in IFNg-treated cells was comparable to core IFNg signaling proteins like IFNGR2, JAK1, JAK2, and STAT1. We validated the involvement of ERK by detecting a sustained increase in phospho-ERK1/2 (p-ERK) levels following IFNg treatment. In live imaging experiments, we found that an ERK inhibitor (ERKi) blocks the induction of cell death in 17 of 23 (~74%) IFNg-sensitive PDM lines covering all the MAPK mutant and triple wildtype molecular subtypes. Through gene expression analysis, we found that IFNg-ERK signaling triggered the expression of stress response genes and subsequent upregulation of DR5 and NOXA, which were both critical for the induction of cell death. In summary, the IFNg-ERK signaling axis mediates cell death downstream of IFNg treatment in melanoma cells. Our results provide a new understanding of the IFNg-mediated GI pathway that will also be crucial to define mechanisms of GI resistance in tumor cells.
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