RESUMEN
To better understand intrinsic resistance to immune checkpoint blockade (ICB), we established a comprehensive view of the cellular architecture of the treatment-naive melanoma ecosystem and studied its evolution under ICB. Using single-cell, spatial multi-omics, we showed that the tumor microenvironment promotes the emergence of a complex melanoma transcriptomic landscape. Melanoma cells harboring a mesenchymal-like (MES) state, a population known to confer resistance to targeted therapy, were significantly enriched in early on-treatment biopsies from non-responders to ICB. TCF4 serves as the hub of this landscape by being a master regulator of the MES signature and a suppressor of the melanocytic and antigen presentation transcriptional programs. Targeting TCF4 genetically or pharmacologically, using a bromodomain inhibitor, increased immunogenicity and sensitivity of MES cells to ICB and targeted therapy. We thereby uncovered a TCF4-dependent regulatory network that orchestrates multiple transcriptional programs and contributes to resistance to both targeted therapy and ICB in melanoma.
Asunto(s)
Melanoma , Humanos , Redes Reguladoras de Genes , Inmunoterapia , Melanocitos , Melanoma/tratamiento farmacológico , Melanoma/genética , Factor de Transcripción 4/genética , Microambiente TumoralRESUMEN
Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.
Asunto(s)
Linfocitos T CD8-positivos , Proteína del Gen 3 de Activación de Linfocitos , Melanoma , Receptor de Muerte Celular Programada 1 , Humanos , Antígenos CD/metabolismo , Antígenos CD/genética , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Citotoxicidad Inmunológica , Proteínas del Grupo de Alta Movilidad , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteína del Gen 3 de Activación de Linfocitos/antagonistas & inhibidores , Melanoma/inmunología , Melanoma/tratamiento farmacológico , Melanoma/genética , Nivolumab/uso terapéutico , Nivolumab/farmacología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Transducción de SeñalRESUMEN
STK19 was proposed to be a cancer driver, and recent work by Yin et al. (2019) in Cell suggested that the frequently recurring STK19 D89N substitution represents a gain-of-function change, allowing increased phosphorylation of NRAS to enhance melanocyte transformation. Here we show that the STK19 gene has been incorrectly annotated, and that the expressed protein is 110 amino acids shorter than indicated by current databases. The "cancer driving" STK19 D89N substitution is thus outside the coding region. We also fail to detect evidence of the mutation affecting STK19 expression; instead, it is a UV signature mutation, found in the promoter of other genes as well. Furthermore, STK19 is exclusively nuclear and chromatin-associated, while no evidence for it being a kinase was found. The data in this Matters Arising article raise fundamental questions about the recently proposed role for STK19 in melanoma progression via a function as an NRAS kinase, suggested by Yin et al. (2019) in Cell. See also the response by Yin et al. (2020), published in this issue.
Asunto(s)
Melanoma , Recurrencia Local de Neoplasia , GTP Fosfohidrolasas/metabolismo , Genes ras , Humanos , Melanoma/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Mutación , Proteínas Nucleares , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Transducción de SeñalRESUMEN
Checkpoint blockade with antibodies specific for the PD-1 and CTLA-4 inhibitory receptors can induce durable responses in a wide range of human cancers. However, the immunological mechanisms responsible for severe inflammatory side effects remain poorly understood. Here we report a comprehensive single-cell analysis of immune cell populations in colitis, a common and severe side effect of checkpoint blockade. We observed a striking accumulation of CD8 T cells with highly cytotoxic and proliferative states and no evidence of regulatory T cell depletion. T cell receptor (TCR) sequence analysis demonstrated that a substantial fraction of colitis-associated CD8 T cells originated from tissue-resident populations, explaining the frequently early onset of colitis symptoms following treatment initiation. Our analysis also identified cytokines, chemokines, and surface receptors that could serve as therapeutic targets for colitis and potentially other inflammatory side effects of checkpoint blockade.
Asunto(s)
Linfocitos T CD8-positivos/citología , Antígeno CTLA-4/inmunología , Colitis/metabolismo , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inmunoterapia/efectos adversos , Células Mieloides/metabolismo , Receptores de Quimiocina/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Antígeno CTLA-4/metabolismo , Quimiocinas/metabolismo , Colitis/tratamiento farmacológico , Colitis/genética , Colitis/inmunología , Citocinas/metabolismo , Citometría de Flujo , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Melanoma/genética , Melanoma/inmunología , Melanoma/metabolismo , Familia de Multigenes , Células Mieloides/citología , RNA-Seq , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Receptores CXCR6/genética , Receptores CXCR6/metabolismo , Receptores de Quimiocina/genética , Análisis de la Célula Individual , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismoRESUMEN
Although clonal neo-antigen burden is associated with improved response to immune therapy, the functional basis for this remains unclear. Here we study this question in a novel controlled mouse melanoma model that enables us to explore the effects of intra-tumor heterogeneity (ITH) on tumor aggressiveness and immunity independent of tumor mutational burden. Induction of UVB-derived mutations yields highly aggressive tumors with decreased anti-tumor activity. However, single-cell-derived tumors with reduced ITH are swiftly rejected. Their rejection is accompanied by increased T cell reactivity and a less suppressive microenvironment. Using phylogenetic analyses and mixing experiments of single-cell clones, we dissect two characteristics of ITH: the number of clones forming the tumor and their clonal diversity. Our analysis of melanoma patient tumor data recapitulates our results in terms of overall survival and response to immune checkpoint therapy. These findings highlight the importance of clonal mutations in robust immune surveillance and the need to quantify patient ITH to determine the response to checkpoint blockade.
Asunto(s)
Heterogeneidad Genética/efectos de la radiación , Melanoma/genética , Melanoma/inmunología , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Rayos Ultravioleta/efectos adversos , Animales , Carcinogénesis/genética , Línea Celular Tumoral , Estudios de Cohortes , Modelos Animales de Enfermedad , Femenino , Humanos , Linfocitos Infiltrantes de Tumor , Melanoma/mortalidad , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos NOD , Ratones Noqueados , Mutación/efectos de la radiación , Filogenia , Neoplasias Cutáneas/mortalidad , Tasa de Supervivencia , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiaciónRESUMEN
Activating mutations in NRAS account for 20%-30% of melanoma, but despite decades of research and in contrast to BRAF, no effective anti-NRAS therapies have been forthcoming. Here, we identify a previously uncharacterized serine/threonine kinase STK19 as a novel NRAS activator. STK19 phosphorylates NRAS to enhance its binding to its downstream effectors and promotes oncogenic NRAS-mediated melanocyte malignant transformation. A recurrent D89N substitution in STK19 whose alterations were identified in 25% of human melanomas represents a gain-of-function mutation that interacts better with NRAS to enhance melanocyte transformation. STK19D89N knockin leads to skin hyperpigmentation and promotes NRASQ61R-driven melanomagenesis in vivo. Finally, we developed ZT-12-037-01 (1a) as a specific STK19-targeted inhibitor and showed that it effectively blocks oncogenic NRAS-driven melanocyte malignant transformation and melanoma growth in vitro and in vivo. Together, our findings provide a new and viable therapeutic strategy for melanomas harboring NRAS mutations.
Asunto(s)
GTP Fosfohidrolasas/metabolismo , Melanoma/genética , Proteínas de la Membrana/metabolismo , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Animales , Línea Celular Tumoral , Transformación Celular Neoplásica , Femenino , Células HEK293 , Humanos , Melanocitos/metabolismo , Melanoma/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Desnudos , Mutación , Fosforilación , Proteínas Proto-Oncogénicas B-raf/metabolismo , Transducción de Señal , Neoplasias Cutáneas/genéticaRESUMEN
Tumor-associated macrophages (TAMs) display pro-tumorigenic phenotypes for supporting tumor progression in response to microenvironmental cues imposed by tumor and stromal cells. However, the underlying mechanisms by which tumor cells instruct TAM behavior remain elusive. Here, we uncover that tumor-cell-derived glucosylceramide stimulated unconventional endoplasmic reticulum (ER) stress responses by inducing reshuffling of lipid composition and saturation on the ER membrane in macrophages, which induced IRE1-mediated spliced XBP1 production and STAT3 activation. The cooperation of spliced XBP1 and STAT3 reinforced the pro-tumorigenic phenotype and expression of immunosuppressive genes. Ablation of XBP1 expression with genetic manipulation or ameliorating ER stress responses by facilitating LPCAT3-mediated incorporation of unsaturated lipids to the phosphatidylcholine hampered pro-tumorigenic phenotype and survival in TAMs. Together, we uncover the unexpected roles of tumor-cell-produced lipids that simultaneously orchestrate macrophage polarization and survival in tumors via induction of ER stress responses and reveal therapeutic targets for sustaining host antitumor immunity.
Asunto(s)
Estrés del Retículo Endoplásmico , Retículo Endoplásmico/metabolismo , Membranas Intracelulares/metabolismo , Activación de Macrófagos , Melanoma/metabolismo , Lípidos de la Membrana/metabolismo , Neoplasias Cutáneas/metabolismo , Macrófagos Asociados a Tumores/metabolismo , Animales , Línea Celular Tumoral , Supervivencia Celular , Retículo Endoplásmico/ultraestructura , Glucosilceramidasa/metabolismo , Membranas Intracelulares/ultraestructura , Melanoma/genética , Melanoma/ultraestructura , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Fenotipo , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/ultraestructura , Escape del Tumor , Microambiente Tumoral , Macrófagos Asociados a Tumores/ultraestructura , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismoRESUMEN
CTLA-4 immune checkpoint blockade is clinically effective in a subset of patients with metastatic melanoma. We identify a subcluster of MAGE-A cancer-germline antigens, located within a narrow 75 kb region of chromosome Xq28, that predicts resistance uniquely to blockade of CTLA-4, but not PD-1. We validate this gene expression signature in an independent anti-CTLA-4-treated cohort and show its specificity to the CTLA-4 pathway with two independent anti-PD-1-treated cohorts. Autophagy, a process critical for optimal anti-cancer immunity, has previously been shown to be suppressed by the MAGE-TRIM28 ubiquitin ligase in vitro. We now show that the expression of the key autophagosome component LC3B and other activators of autophagy are negatively associated with MAGE-A protein levels in human melanomas, including samples from patients with resistance to CTLA-4 blockade. Our findings implicate autophagy suppression in resistance to CTLA-4 blockade in melanoma, suggesting exploitation of autophagy induction for potential therapeutic synergy with CTLA-4 inhibitors.
Asunto(s)
Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Epigénesis Genética , Mutación de Línea Germinal , Neoplasias/genética , Neoplasias/inmunología , Animales , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Autofagia , Línea Celular Tumoral , Metilación de ADN , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunoterapia , Ipilimumab/farmacología , Masculino , Melanoma/genética , Melanoma/inmunología , Antígenos Específicos del Melanoma/genética , Antígenos Específicos del Melanoma/inmunología , Ratones , Ratones Transgénicos , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunologíaRESUMEN
Conventional type 1 dendritic cells (cDC1) are critical for antitumor immunity, and their abundance within tumors is associated with immune-mediated rejection and the success of immunotherapy. Here, we show that cDC1 accumulation in mouse tumors often depends on natural killer (NK) cells that produce the cDC1 chemoattractants CCL5 and XCL1. Similarly, in human cancers, intratumoral CCL5, XCL1, and XCL2 transcripts closely correlate with gene signatures of both NK cells and cDC1 and are associated with increased overall patient survival. Notably, tumor production of prostaglandin E2 (PGE2) leads to evasion of the NK cell-cDC1 axis in part by impairing NK cell viability and chemokine production, as well as by causing downregulation of chemokine receptor expression in cDC1. Our findings reveal a cellular and molecular checkpoint for intratumoral cDC1 recruitment that is targeted by tumor-derived PGE2 for immune evasion and that could be exploited for cancer therapy.
Asunto(s)
Células Dendríticas/inmunología , Células Asesinas Naturales/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología , Animales , Línea Celular Tumoral , Quimiocina CCL5/metabolismo , Quimiocinas C/metabolismo , Ciclooxigenasa 1/metabolismo , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Regulación Neoplásica de la Expresión Génica , Humanos , Melanoma/genética , Melanoma/patología , Ratones , Mutación/genética , Pronóstico , Proteínas Proto-Oncogénicas B-raf/genética , Análisis de SupervivenciaRESUMEN
BRAF(V600E) mutant melanomas treated with inhibitors of the BRAF and MEK kinases almost invariably develop resistance that is frequently caused by reactivation of the mitogen activated protein kinase (MAPK) pathway. To identify novel treatment options for such patients, we searched for acquired vulnerabilities of MAPK inhibitor-resistant melanomas. We find that resistance to BRAF+MEK inhibitors is associated with increased levels of reactive oxygen species (ROS). Subsequent treatment with the histone deacetylase inhibitor vorinostat suppresses SLC7A11, leading to a lethal increase in the already-elevated levels of ROS in drug-resistant cells. This causes selective apoptotic death of only the drug-resistant tumor cells. Consistently, treatment of BRAF inhibitor-resistant melanoma with vorinostat in mice results in dramatic tumor regression. In a study in patients with advanced BRAF+MEK inhibitor-resistant melanoma, we find that vorinostat can selectively ablate drug-resistant tumor cells, providing clinical proof of concept for the novel therapy identified here.
Asunto(s)
Resistencia a Antineoplásicos , Melanoma/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Sistema de Transporte de Aminoácidos y+/metabolismo , Animales , Apoptosis , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Humanos , MAP Quinasa Quinasa 1/metabolismo , Sistema de Señalización de MAP Quinasas , Melanoma/genética , Ratones , Mutación , Trasplante de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas B-raf/genética , Especies Reactivas de Oxígeno/metabolismo , Neoplasias Cutáneas/genética , Resultado del Tratamiento , Vorinostat/farmacologíaRESUMEN
The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumab-naive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Inmunoterapia , Melanoma/terapia , Microambiente Tumoral , Estudio de Asociación del Genoma Completo , Humanos , Melanoma/genética , Melanoma/inmunología , Nivolumab , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Linfocitos T , TranscriptomaRESUMEN
Many processes can cause the same nucleotide change in a genome, making the identification of the mechanisms causing mutations a difficult challenge. Here, we show that clustered mutations provide a more precise fingerprint of mutagenic processes. Of nine clustered mutation signatures identified from >1,000 tumor genomes, three relate to variable APOBEC activity and three are associated with tobacco smoking. An additional signature matches the spectrum of translesion DNA polymerase eta (POLH). In lymphoid cells, these mutations target promoters, consistent with AID-initiated somatic hypermutation. In solid tumors, however, they are associated with UV exposure and alcohol consumption and target the H3K36me3 chromatin of active genes in a mismatch repair (MMR)-dependent manner. These regions normally have a low mutation rate because error-free MMR also targets H3K36me3 chromatin. Carcinogens and error-prone repair therefore redistribute mutations to the more important regions of the genome, contributing a substantial mutation load in many tumors, including driver mutations.
Asunto(s)
Reparación de la Incompatibilidad de ADN , Mutación , Neoplasias/genética , Desaminasas APOBEC , Citidina Desaminasa , Citosina Desaminasa/genética , ADN Polimerasa Dirigida por ADN/genética , Humanos , Neoplasias Hepáticas/inducido químicamente , Neoplasias Hepáticas/genética , Melanoma/genética , Mutagénesis , Fumar/efectos adversos , Rayos Ultravioleta/efectos adversosRESUMEN
Homeostatic programs balance immune protection and self-tolerance. Such mechanisms likely impact autoimmunity and tumor formation, respectively. How homeostasis is maintained and impacts tumor surveillance is unknown. Here, we find that different immune mononuclear phagocytes share a conserved steady-state program during differentiation and entry into healthy tissue. IFNγ is necessary and sufficient to induce this program, revealing a key instructive role. Remarkably, homeostatic and IFNγ-dependent programs enrich across primary human tumors, including melanoma, and stratify survival. Single-cell RNA sequencing (RNA-seq) reveals enrichment of homeostatic modules in monocytes and DCs from human metastatic melanoma. Suppressor-of-cytokine-2 (SOCS2) protein, a conserved program transcript, is expressed by mononuclear phagocytes infiltrating primary melanoma and is induced by IFNγ. SOCS2 limits adaptive anti-tumoral immunity and DC-based priming of T cells in vivo, indicating a critical regulatory role. These findings link immune homeostasis to key determinants of anti-tumoral immunity and escape, revealing co-opting of tissue-specific immune development in the tumor microenvironment.
Asunto(s)
Interferón gamma/inmunología , Melanoma/inmunología , Monocitos/inmunología , Metástasis de la Neoplasia/patología , Neoplasias Cutáneas/inmunología , Proteínas Supresoras de la Señalización de Citocinas/metabolismo , Microambiente Tumoral , Animales , Diferenciación Celular , Células Dendríticas/inmunología , Homeostasis , Humanos , Melanoma/genética , Melanoma/patología , Ratones , Monocitos/patología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , TranscriptomaRESUMEN
Since genome instability can drive cancer initiation and progression, cells have evolved highly effective and ubiquitous DNA damage response (DDR) programs. However, some cells (for example, in skin) are normally exposed to high levels of DNA-damaging agents. Whether such high-risk cells possess lineage-specific mechanisms that tailor DNA repair to the tissue remains largely unknown. Using melanoma as a model, we show here that the microphthalmia-associated transcription factor MITF, a lineage addition oncogene that coordinates many aspects of melanocyte and melanoma biology, plays a nontranscriptional role in shaping the DDR. On exposure to DNA-damaging agents, MITF is phosphorylated at S325, and its interactome is dramatically remodeled; most transcription cofactors dissociate, and instead MITF interacts with the MRE11-RAD50-NBS1 (MRN) complex. Consequently, cells with high MITF levels accumulate stalled replication forks and display defects in homologous recombination-mediated repair associated with impaired MRN recruitment to DNA damage. In agreement with this, high MITF levels are associated with increased single-nucleotide and copy number variant burdens in melanoma. Significantly, the SUMOylation-defective MITF-E318K melanoma predisposition mutation recapitulates the effects of DNA-PKcs-phosphorylated MITF. Our data suggest that a nontranscriptional function of a lineage-restricted transcription factor contributes to a tissue-specialized modulation of the DDR that can impact cancer initiation.
Asunto(s)
Melanoma , Humanos , Melanoma/genética , Factor de Transcripción Asociado a Microftalmía/genética , Daño del ADN , Inestabilidad Genómica/genética , ADNRESUMEN
High levels of H2A.Z promote melanoma cell proliferation and correlate with poor prognosis. However, the role of the two distinct H2A.Z histone chaperone complexes SRCAP and P400-TIP60 in melanoma remains unclear. Here, we show that individual subunit depletion of SRCAP, P400, and VPS72 (YL1) results in not only the loss of H2A.Z deposition into chromatin but also a reduction of H4 acetylation in melanoma cells. This loss of H4 acetylation is particularly found at the promoters of cell cycle genes directly bound by H2A.Z and its chaperones, suggesting a coordinated regulation between H2A.Z deposition and H4 acetylation to promote their expression. Knockdown of each of the three subunits downregulates E2F1 and its targets, resulting in a cell cycle arrest akin to H2A.Z depletion. However, unlike H2A.Z deficiency, loss of the shared H2A.Z chaperone subunit YL1 induces apoptosis. Furthermore, YL1 is overexpressed in melanoma tissues, and its upregulation is associated with poor patient outcome. Together, these findings provide a rationale for future targeting of H2A.Z chaperones as an epigenetic strategy for melanoma treatment.
Asunto(s)
Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Histonas , Melanoma , Humanos , Melanoma/genética , Proliferación Celular/genética , Línea Celular Tumoral , Histonas/metabolismo , Histonas/genética , Acetilación , Apoptosis/genética , Factor de Transcripción E2F1/metabolismo , Factor de Transcripción E2F1/genética , Chaperonas Moleculares/metabolismo , Chaperonas Moleculares/genéticaRESUMEN
PD-1 immune checkpoint blockade provides significant clinical benefits for melanoma patients. We analyzed the somatic mutanomes and transcriptomes of pretreatment melanoma biopsies to identify factors that may influence innate sensitivity or resistance to anti-PD-1 therapy. We find that overall high mutational loads associate with improved survival, and tumors from responding patients are enriched for mutations in the DNA repair gene BRCA2. Innately resistant tumors display a transcriptional signature (referred to as the IPRES, or innate anti-PD-1 resistance), indicating concurrent up-expression of genes involved in the regulation of mesenchymal transition, cell adhesion, extracellular matrix remodeling, angiogenesis, and wound healing. Notably, mitogen-activated protein kinase (MAPK)-targeted therapy (MAPK inhibitor) induces similar signatures in melanoma, suggesting that a non-genomic form of MAPK inhibitor resistance mediates cross-resistance to anti-PD-1 therapy. Validation of the IPRES in other independent tumor cohorts defines a transcriptomic subset across distinct types of advanced cancer. These findings suggest that attenuating the biological processes that underlie IPRES may improve anti-PD-1 response in melanoma and other cancer types.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Resistencia a Antineoplásicos , Melanoma/tratamiento farmacológico , Metástasis de la Neoplasia/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos/efectos adversos , Proteína BRCA2/genética , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Melanoma/genética , Metástasis de la Neoplasia/genética , Nivolumab , TranscriptomaRESUMEN
Antibody blockade of the inhibitory CTLA-4 pathway has led to clinical benefit in a subset of patients with metastatic melanoma. Anti-CTLA-4 enhances T cell responses, including production of IFN-γ, which is a critical cytokine for host immune responses. However, the role of IFN-γ signaling in tumor cells in the setting of anti-CTLA-4 therapy remains unknown. Here, we demonstrate that patients identified as non-responders to anti-CTLA-4 (ipilimumab) have tumors with genomic defects in IFN-γ pathway genes. Furthermore, mice bearing melanoma tumors with knockdown of IFN-γ receptor 1 (IFNGR1) have impaired tumor rejection upon anti-CTLA-4 therapy. These data highlight that loss of the IFN-γ signaling pathway is associated with primary resistance to anti-CTLA-4 therapy. Our findings demonstrate the importance of tumor genomic data, especially IFN-γ related genes, as prognostic information for patients selected to receive treatment with immune checkpoint therapy.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Antígeno CTLA-4/antagonistas & inhibidores , Resistencia a Antineoplásicos/genética , Interferón gamma/genética , Melanoma/tratamiento farmacológico , Receptores de Interferón/genética , Neoplasias Cutáneas/tratamiento farmacológico , Animales , Línea Celular Tumoral , Citocinas/inmunología , Técnicas de Silenciamiento del Gen , Humanos , Ipilimumab , Melanoma/genética , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/genética , Ratones , Ratones Endogámicos C57BL , Neoplasias Cutáneas/genética , Linfocitos T/inmunología , Receptor de Interferón gammaRESUMEN
MYC's key role in oncogenesis and tumor progression has long been established for most human cancers. In melanoma, its deregulated activity by amplification of 8q24 chromosome or by upstream signaling coming from activating mutations in the RAS/RAF/MAPK pathway-the most predominantly mutated pathway in this disease-turns MYC into not only a driver but also a facilitator of melanoma progression, with documented effects leading to an aggressive clinical course and resistance to targeted therapy. Here, by making use of Omomyc, the most characterized MYC inhibitor to date that has just successfully completed a phase I clinical trial, we show for the first time that MYC inhibition in melanoma induces remarkable transcriptional modulation, resulting in severely compromised tumor growth and a clear abrogation of metastatic capacity independently of the driver mutation. By reducing MYC's transcriptional footprint in melanoma, Omomyc elicits gene expression profiles remarkably similar to those of patients with good prognosis, underlining the therapeutic potential that such an approach could eventually have in the clinic in this dismal disease.
Asunto(s)
Melanoma , Humanos , Pronóstico , Melanoma/genética , Transducción de Señal , Carcinogénesis , Transformación Celular Neoplásica , Proteínas Proto-Oncogénicas c-myc/metabolismoRESUMEN
We describe the landscape of genomic alterations in cutaneous melanomas through DNA, RNA, and protein-based analysis of 333 primary and/or metastatic melanomas from 331 patients. We establish a framework for genomic classification into one of four subtypes based on the pattern of the most prevalent significantly mutated genes: mutant BRAF, mutant RAS, mutant NF1, and Triple-WT (wild-type). Integrative analysis reveals enrichment of KIT mutations and focal amplifications and complex structural rearrangements as a feature of the Triple-WT subtype. We found no significant outcome correlation with genomic classification, but samples assigned a transcriptomic subclass enriched for immune gene expression associated with lymphocyte infiltrate on pathology review and high LCK protein expression, a T cell marker, were associated with improved patient survival. This clinicopathological and multi-dimensional analysis suggests that the prognosis of melanoma patients with regional metastases is influenced by tumor stroma immunobiology, offering insights to further personalize therapeutic decision-making.