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1.
Cell ; 185(10): 1694-1708.e19, 2022 05 12.
Artículo en Inglés | MEDLINE | ID: mdl-35447074

RESUMEN

Immunotherapy is a promising treatment for triple-negative breast cancer (TNBC), but patients relapse, highlighting the need to understand the mechanisms of resistance. We discovered that in primary breast cancer, tumor cells that resist T cell attack are quiescent. Quiescent cancer cells (QCCs) form clusters with reduced immune infiltration. They also display superior tumorigenic capacity and higher expression of chemotherapy resistance and stemness genes. We adapted single-cell RNA-sequencing with precise spatial resolution to profile infiltrating cells inside and outside the QCC niche. This transcriptomic analysis revealed hypoxia-induced programs and identified more exhausted T cells, tumor-protective fibroblasts, and dysfunctional dendritic cells inside clusters of QCCs. This uncovered differential phenotypes in infiltrating cells based on their intra-tumor location. Thus, QCCs constitute immunotherapy-resistant reservoirs by orchestrating a local hypoxic immune-suppressive milieu that blocks T cell function. Eliminating QCCs holds the promise to counteract immunotherapy resistance and prevent disease recurrence in TNBC.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Inmunosupresores/uso terapéutico , Inmunoterapia , Recurrencia Local de Neoplasia , Linfocitos T/patología , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral
2.
Cell ; 173(3): 624-633.e8, 2018 04 19.
Artículo en Inglés | MEDLINE | ID: mdl-29656892

RESUMEN

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/inmunología
3.
Cell ; 171(3): 540-556.e25, 2017 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-28988769

RESUMEN

We report a comprehensive analysis of 412 muscle-invasive bladder cancers characterized by multiple TCGA analytical platforms. Fifty-eight genes were significantly mutated, and the overall mutational load was associated with APOBEC-signature mutagenesis. Clustering by mutation signature identified a high-mutation subset with 75% 5-year survival. mRNA expression clustering refined prior clustering analyses and identified a poor-survival "neuronal" subtype in which the majority of tumors lacked small cell or neuroendocrine histology. Clustering by mRNA, long non-coding RNA (lncRNA), and miRNA expression converged to identify subsets with differential epithelial-mesenchymal transition status, carcinoma in situ scores, histologic features, and survival. Our analyses identified 5 expression subtypes that may stratify response to different treatments.


Asunto(s)
Neoplasias de la Vejiga Urinaria/genética , Neoplasias de la Vejiga Urinaria/patología , Anciano , Análisis por Conglomerados , Metilación de ADN , Humanos , MicroARNs/genética , Persona de Mediana Edad , Músculo Liso/patología , ARN Largo no Codificante/genética , Análisis de Supervivencia , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/terapia
4.
Cell ; 160(1-2): 48-61, 2015 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-25594174

RESUMEN

How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity.


Asunto(s)
Neoplasias/inmunología , Presentación de Antígeno , Antígenos de Neoplasias/inmunología , Apoptosis , Variaciones en el Número de Copia de ADN , Bases de Datos Genéticas , Retrovirus Endógenos , Genoma Humano , Humanos , Mutación , Necrosis , Neoplasias/patología , Linfocitos T Citotóxicos/inmunología
5.
Cell ; 152(4): 714-26, 2013 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-23415222

RESUMEN

Clonal evolution is a key feature of cancer progression and relapse. We studied intratumoral heterogeneity in 149 chronic lymphocytic leukemia (CLL) cases by integrating whole-exome sequence and copy number to measure the fraction of cancer cells harboring each somatic mutation. We identified driver mutations as predominantly clonal (e.g., MYD88, trisomy 12, and del(13q)) or subclonal (e.g., SF3B1 and TP53), corresponding to earlier and later events in CLL evolution. We sampled leukemia cells from 18 patients at two time points. Ten of twelve CLL cases treated with chemotherapy (but only one of six without treatment) underwent clonal evolution, predominantly involving subclones with driver mutations (e.g., SF3B1 and TP53) that expanded over time. Furthermore, presence of a subclonal driver mutation was an independent risk factor for rapid disease progression. Our study thus uncovers patterns of clonal evolution in CLL, providing insights into its stepwise transformation, and links the presence of subclones with adverse clinical outcomes.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Mutación , Algoritmos , Animales , Linfocitos B/metabolismo , Variaciones en el Número de Copia de ADN , Estudio de Asociación del Genoma Completo , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Ploidias
7.
Cell ; 155(2): 462-77, 2013 Oct 10.
Artículo en Inglés | MEDLINE | ID: mdl-24120142

RESUMEN

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer.


Asunto(s)
Neoplasias Encefálicas/genética , Glioblastoma/genética , Neoplasias Encefálicas/metabolismo , Femenino , Perfilación de la Expresión Génica , Redes Reguladoras de Genes , Glioblastoma/metabolismo , Humanos , Masculino , Mutación , Proteoma/análisis , Transducción de Señal
8.
Nature ; 596(7870): 119-125, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34290406

RESUMEN

Interactions between T cell receptors (TCRs) and their cognate tumour antigens are central to antitumour immune responses1-3; however, the relationship between phenotypic characteristics and TCR properties is not well elucidated. Here we show, by linking the antigenic specificity of TCRs and the cellular phenotype of melanoma-infiltrating lymphocytes at single-cell resolution, that tumour specificity shapes the expression state of intratumoural CD8+ T cells. Non-tumour-reactive T cells were enriched for viral specificities and exhibited a non-exhausted memory phenotype, whereas melanoma-reactive lymphocytes predominantly displayed an exhausted state that encompassed diverse levels of differentiation but rarely acquired memory properties. These exhausted phenotypes were observed both among clonotypes specific for public overexpressed melanoma antigens (shared across different tumours) or personal neoantigens (specific for each tumour). The recognition of such tumour antigens was provided by TCRs with avidities inversely related to the abundance of cognate targets in melanoma cells and proportional to the binding affinity of peptide-human leukocyte antigen (HLA) complexes. The persistence of TCR clonotypes in peripheral blood was negatively affected by the level of intratumoural exhaustion, and increased in patients with a poor response to immune checkpoint blockade, consistent with chronic stimulation mediated by residual tumour antigens. By revealing how the quality and quantity of tumour antigens drive the features of T cell responses within the tumour microenvironment, we gain insights into the properties of the anti-melanoma TCR repertoire.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Melanoma/inmunología , Especificidad por Sustrato/inmunología , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Conjuntos de Datos como Asunto , Regulación de la Expresión Génica , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Melanoma/sangre , Fenotipo , Receptores de Antígenos de Linfocitos T/inmunología , Análisis de la Célula Individual , Transcriptoma/genética , Microambiente Tumoral
9.
Nature ; 565(7738): 234-239, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30568305

RESUMEN

Neoantigens, which are derived from tumour-specific protein-coding mutations, are exempt from central tolerance, can generate robust immune responses1,2 and can function as bona fide antigens that facilitate tumour rejection3. Here we demonstrate that a strategy that uses multi-epitope, personalized neoantigen vaccination, which has previously been tested in patients with high-risk melanoma4-6, is feasible for tumours such as glioblastoma, which typically have a relatively low mutation load1,7 and an immunologically 'cold' tumour microenvironment8. We used personalized neoantigen-targeting vaccines to immunize patients newly diagnosed with glioblastoma following surgical resection and conventional radiotherapy in a phase I/Ib study. Patients who did not receive dexamethasone-a highly potent corticosteroid that is frequently prescribed to treat cerebral oedema in patients with glioblastoma-generated circulating polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses that were enriched in a memory phenotype and showed an increase in the number of tumour-infiltrating T cells. Using single-cell T cell receptor analysis, we provide evidence that neoantigen-specific T cells from the peripheral blood can migrate into an intracranial glioblastoma tumour. Neoantigen-targeting vaccines thus have the potential to favourably alter the immune milieu of glioblastoma.


Asunto(s)
Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Glioblastoma/inmunología , Glioblastoma/terapia , Linfocitos T/inmunología , Adulto , Anciano , Metilación de ADN , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Dexametasona/administración & dosificación , Glioblastoma/diagnóstico , Glioblastoma/genética , Humanos , Persona de Mediana Edad , Regiones Promotoras Genéticas/genética , Receptores de Antígenos de Linfocitos T/inmunología , Proteínas Supresoras de Tumor/genética , Adulto Joven
11.
Nature ; 547(7662): 217-221, 2017 07 13.
Artículo en Inglés | MEDLINE | ID: mdl-28678778

RESUMEN

Effective anti-tumour immunity in humans has been associated with the presence of T cells directed at cancer neoantigens, a class of HLA-bound peptides that arise from tumour-specific mutations. They are highly immunogenic because they are not present in normal tissues and hence bypass central thymic tolerance. Although neoantigens were long-envisioned as optimal targets for an anti-tumour immune response, their systematic discovery and evaluation only became feasible with the recent availability of massively parallel sequencing for detection of all coding mutations within tumours, and of machine learning approaches to reliably predict those mutated peptides with high-affinity binding of autologous human leukocyte antigen (HLA) molecules. We hypothesized that vaccination with neoantigens can both expand pre-existing neoantigen-specific T-cell populations and induce a broader repertoire of new T-cell specificities in cancer patients, tipping the intra-tumoural balance in favour of enhanced tumour control. Here we demonstrate the feasibility, safety, and immunogenicity of a vaccine that targets up to 20 predicted personal tumour neoantigens. Vaccine-induced polyfunctional CD4+ and CD8+ T cells targeted 58 (60%) and 15 (16%) of the 97 unique neoantigens used across patients, respectively. These T cells discriminated mutated from wild-type antigens, and in some cases directly recognized autologous tumour. Of six vaccinated patients, four had no recurrence at 25 months after vaccination, while two with recurrent disease were subsequently treated with anti-PD-1 (anti-programmed cell death-1) therapy and experienced complete tumour regression, with expansion of the repertoire of neoantigen-specific T cells. These data provide a strong rationale for further development of this approach, alone and in combination with checkpoint blockade or other immunotherapies.


Asunto(s)
Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Melanoma/inmunología , Melanoma/terapia , Medicina de Precisión/métodos , Secuencia de Aminoácidos , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antígenos de Neoplasias/química , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer/efectos adversos , Vacunas contra el Cáncer/química , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Aprendizaje Automático , Melanoma/genética , Mutación , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/prevención & control , Seguridad del Paciente , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores
12.
Lancet Oncol ; 23(1): 172-184, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34895481

RESUMEN

BACKGROUND: Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. METHODS: In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). FINDINGS: HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20-1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05-1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01-1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01-1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16-2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0·76) INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. FUNDING: National Institutes of Health, Merck KGaA, and Pfizer.


Asunto(s)
Antígeno HLA-A3/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Alelos , Biomarcadores , Estudios Epidemiológicos , Humanos , Neoplasias/inmunología , Neoplasias/mortalidad
13.
Genome Res ; 27(8): 1300-1311, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28679620

RESUMEN

Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype-phenotype relationships, we developed methods for targeted mutation detection in DNA and RNA isolated from thousands of single cells from five CLL samples. By clearly resolving phylogenic relationships, we uncovered mutated LCP1 and WNK1 as novel CLL drivers, supported by functional evidence demonstrating their impact on CLL pathways. Integrative analysis of somatic mutations with transcriptional states prompts the idea that convergent evolution generates phenotypically similar cells in distinct genetic branches, thus creating a cohesive expression profile in each CLL sample despite the presence of genetic heterogeneity. Our study highlights the potential for single-cell RNA-based targeted analysis to sensitively determine transcriptional and mutational profiles of individual cancer cells, leading to increased understanding of driving events in malignancy.


Asunto(s)
Biomarcadores de Tumor/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Mutación , Análisis de Secuencia de ADN/métodos , Análisis de la Célula Individual/métodos , Adulto , Estudios de Casos y Controles , Evolución Molecular , Femenino , Humanos , Masculino , Persona de Mediana Edad , Transcripción Genética
14.
Blood ; 132(18): 1911-1921, 2018 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-30150207

RESUMEN

Recent studies have highlighted the promise of targeting tumor neoantigens to generate potent antitumor immune responses and provide strong motivation for improving our understanding of antigen-T-cell receptor (TCR) interactions. Advances in single-cell sequencing technologies have opened the door for detailed investigation of the TCR repertoire, providing paired information from TCRα and TCRß, which together determine specificity. However, a need remains for efficient methods to assess the specificity of discovered TCRs. We developed a streamlined approach for matching TCR sequences with cognate antigen through on-demand cloning and expression of TCRs and screening against candidate antigens. Here, we first demonstrate the system's capacity to identify viral-antigen-specific TCRs and compare the functional avidity of TCRs specific for a given antigen target. We then apply this system to identify neoantigen-specific TCR sequences from patients with melanoma treated with personalized neoantigen vaccines and characterize functional avidity of neoantigen-specific TCRs. Furthermore, we use a neoantigen-prediction pipeline to show that an insertion-deletion mutation in a putative chronic lymphocytic leukemia (CLL) driver gives rise to an immunogenic neoantigen mut-MGA, and use this approach to identify the mut-MGA-specific TCR sequence. This approach provides a means to identify and express TCRs, and then rapidly assess antigen specificity and functional avidity of a reconstructed TCR, which can be applied for monitoring antigen-specific T-cell responses, and potentially for guiding the design of effective T-cell-based immunotherapies.


Asunto(s)
Antígenos de Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T , Vacunas contra el Cáncer/uso terapéutico , Células Cultivadas , Clonación Molecular/métodos , Células HEK293 , Humanos , Células Jurkat , Leucemia Linfocítica Crónica de Células B/inmunología , Melanoma/inmunología , Melanoma/terapia , Receptores de Antígenos de Linfocitos T/genética
15.
Genes Dev ; 26(13): 1459-72, 2012 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-22751500

RESUMEN

Multidimensional cancer genome analysis and validation has defined Quaking (QKI), a member of the signal transduction and activation of RNA (STAR) family of RNA-binding proteins, as a novel glioblastoma multiforme (GBM) tumor suppressor. Here, we establish that p53 directly regulates QKI gene expression, and QKI protein associates with and leads to the stabilization of miR-20a; miR-20a, in turn, regulates TGFßR2 and the TGFß signaling network. This pathway circuitry is substantiated by in silico epistasis analysis of its components in the human GBM TCGA (The Cancer Genome Atlas Project) collection and by their gain- and loss-of-function interactions in in vitro and in vivo complementation studies. This p53-QKI-miR-20a-TGFß pathway expands our understanding of the p53 tumor suppression network in cancer and reveals a novel tumor suppression mechanism involving regulation of specific cancer-relevant microRNAs.


Asunto(s)
Línea Celular , Glioblastoma/metabolismo , MicroARNs/metabolismo , Estabilidad del ARN , Proteínas de Unión al ARN/metabolismo , Animales , Glioblastoma/genética , Humanos , Ratones , MicroARNs/genética , Proteínas de Unión al ARN/genética , Transducción de Señal , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
16.
Cancer Immunol Immunother ; 68(3): 421-432, 2019 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-30564891

RESUMEN

Targeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tail containing a cysteine that allows it to homodimerize and more effectively inhibit lymphocyte function than monomeric soluble PD-L1. We show that recombinant secPD-L1 can dimerize and inhibit T-cell proliferation and IFN-gamma production in vitro. The secPD-L1 variant is expressed by malignant cells in vitro that also express high levels of full-length PD-L1. Transcriptomic analysis of gene expression across The Cancer Genome Atlas found the strongest association of secPD-L1 with full-length PD-L1, but also with subsets of immunologic genes, such as in myeloid-derived suppressor cells. Moreover, the splice variant is also expressed in normal tissues and within normal peripheral blood cells it is preferentially expressed in activated myeloid cells. This is the first report of a form of secreted PD-L1 that homodimerizes and is functionally active. SecPD-L1 may function as a paracrine negative immune regulator within the tumor, since secPD-L1 does not require a cell-to-cell interaction to mediate its inhibitory effect.


Asunto(s)
Antígeno B7-H1/genética , Inmunosupresores/farmacología , Multimerización de Proteína , Empalme del ARN , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/química , Antígeno B7-H1/farmacología , Línea Celular Tumoral , Femenino , Perfilación de la Expresión Génica , Humanos , Células Supresoras de Origen Mieloide/fisiología , Placenta/metabolismo , Embarazo , Microambiente Tumoral
17.
Nature ; 470(7334): 359-65, 2011 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-21307849

RESUMEN

Telomere dysfunction activates p53-mediated cellular growth arrest, senescence and apoptosis to drive progressive atrophy and functional decline in high-turnover tissues. The broader adverse impact of telomere dysfunction across many tissues including more quiescent systems prompted transcriptomic network analyses to identify common mechanisms operative in haematopoietic stem cells, heart and liver. These unbiased studies revealed profound repression of peroxisome proliferator-activated receptor gamma, coactivator 1 alpha and beta (PGC-1α and PGC-1ß, also known as Ppargc1a and Ppargc1b, respectively) and the downstream network in mice null for either telomerase reverse transcriptase (Tert) or telomerase RNA component (Terc) genes. Consistent with PGCs as master regulators of mitochondrial physiology and metabolism, telomere dysfunction is associated with impaired mitochondrial biogenesis and function, decreased gluconeogenesis, cardiomyopathy, and increased reactive oxygen species. In the setting of telomere dysfunction, enforced Tert or PGC-1α expression or germline deletion of p53 (also known as Trp53) substantially restores PGC network expression, mitochondrial respiration, cardiac function and gluconeogenesis. We demonstrate that telomere dysfunction activates p53 which in turn binds and represses PGC-1α and PGC-1ß promoters, thereby forging a direct link between telomere and mitochondrial biology. We propose that this telomere-p53-PGC axis contributes to organ and metabolic failure and to diminishing organismal fitness in the setting of telomere dysfunction.


Asunto(s)
Mitocondrias/metabolismo , Mitocondrias/patología , Telómero/metabolismo , Telómero/patología , Adenosina Trifosfato/biosíntesis , Envejecimiento/metabolismo , Envejecimiento/patología , Animales , Cardiomiopatías/inducido químicamente , Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Cardiomiopatías/fisiopatología , Proliferación Celular , ADN Mitocondrial/análisis , Doxorrubicina/toxicidad , Gluconeogénesis , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/patología , Hígado/citología , Hígado/metabolismo , Ratones , Miocardio/citología , Miocardio/metabolismo , ARN/genética , Especies Reactivas de Oxígeno/metabolismo , Telomerasa/deficiencia , Telomerasa/genética , Telómero/enzimología , Telómero/genética , Factores de Transcripción/antagonistas & inhibidores , Factores de Transcripción/metabolismo , Proteína p53 Supresora de Tumor/deficiencia , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo
18.
Blood ; 124(3): 453-62, 2014 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-24891321

RESUMEN

Genome sequencing has revealed a large number of shared and personal somatic mutations across human cancers. In principle, any genetic alteration affecting a protein-coding region has the potential to generate mutated peptides that are presented by surface HLA class I proteins that might be recognized by cytotoxic T cells. To test this possibility, we implemented a streamlined approach for the prediction and validation of such neoantigens derived from individual tumors and presented by patient-specific HLA alleles. We applied our computational pipeline to 91 chronic lymphocytic leukemias (CLLs) that underwent whole-exome sequencing (WES). We predicted ∼22 mutated HLA-binding peptides per leukemia (derived from ∼16 missense mutations) and experimentally confirmed HLA binding for ∼55% of such peptides. Two CLL patients that achieved long-term remission following allogeneic hematopoietic stem cell transplantation were monitored for CD8(+) T-cell responses against predicted or confirmed HLA-binding peptides. Long-lived cytotoxic T-cell responses were detected against peptides generated from personal tumor mutations in ALMS1, C6ORF89, and FNDC3B presented on tumor cells. Finally, we applied our computational pipeline to WES data (N = 2488 samples) across 13 different cancer types and estimated dozens to thousands of predicted neoantigens per individual tumor, suggesting that neoantigens are frequent in most tumors.


Asunto(s)
Antígenos de Neoplasias/genética , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Mutación , Antígenos de Neoplasias/metabolismo , Vacunas contra el Cáncer/genética , Vacunas contra el Cáncer/inmunología , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/metabolismo , Exoma , Femenino , Antígenos HLA/metabolismo , Humanos , Memoria Inmunológica , Leucemia Linfocítica Crónica de Células B/terapia , Masculino , Medicina de Precisión , Unión Proteica , Linfocitos T Citotóxicos/inmunología
19.
Blood ; 124(7): 1089-98, 2014 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-24778153

RESUMEN

One major goal of cancer genome sequencing is to identify key genes and pathways that drive tumor pathogenesis. Although many studies have identified candidate driver genes based on recurrence of mutations in individual genes, subsets of genes with nonrecurrent mutations may also be defined as putative drivers if they affect a single biological pathway. In this fashion, we previously identified Wnt signaling as significantly mutated through large-scale massively parallel DNA sequencing of chronic lymphocytic leukemia (CLL). Here, we use a novel method of biomolecule delivery, vertical silicon nanowires, to efficiently introduce small interfering RNAs into CLL cells, and interrogate the effects of 8 of 15 mutated Wnt pathway members identified across 91 CLLs. In HEK293T cells, mutations in 2 genes did not generate functional changes, 3 led to dysregulated pathway activation, and 3 led to further activation or loss of repression of pathway activation. Silencing 4 of 8 mutated genes in CLL samples harboring the mutated alleles resulted in reduced viability compared with leukemia samples with wild-type alleles. We demonstrate that somatic mutations in CLL can generate dependence on this pathway for survival. These findings support the notion that nonrecurrent mutations at different nodes of the Wnt pathway can contribute to leukemogenesis.


Asunto(s)
Leucemia Linfocítica Crónica de Células B/genética , Mutación , Transducción de Señal/genética , Vía de Señalización Wnt/genética , beta Catenina/metabolismo , Adulto , Línea Celular Tumoral , Supervivencia Celular/genética , Células Cultivadas , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Células HEK293 , Humanos , Leucemia Linfocítica Crónica de Células B/metabolismo , Leucemia Linfocítica Crónica de Células B/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Interferencia de ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa
20.
Cancer Cell ; 42(5): 732-735, 2024 May 13.
Artículo en Inglés | MEDLINE | ID: mdl-38579722

RESUMEN

Saliby et al. show that a machine learning approach can accurately classify clear cell renal cell carcinoma (RCC) into distinct molecular subtypes using transcriptomic data. When applied to tumors biospecimens from the JAVELIN Renal 101 (JR101) trial, a benefit is observed with immune checkpoint inhibitor (ICI)-based therapy across all molecular subtypes.


Asunto(s)
Carcinoma de Células Renales , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Renales , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/terapia , Carcinoma de Células Renales/tratamiento farmacológico , Humanos , Neoplasias Renales/inmunología , Neoplasias Renales/genética , Neoplasias Renales/terapia , Neoplasias Renales/tratamiento farmacológico , Inmunoterapia/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Terapia Molecular Dirigida/métodos , Resultado del Tratamiento , Aprendizaje Automático
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