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1.
Cell ; 184(18): 4734-4752.e20, 2021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34450029

RESUMO

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.


Assuntos
Neoplasias Colorretais/imunologia , Neoplasias Colorretais/patologia , Proteínas Morfogenéticas Ósseas/metabolismo , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Compartimento Celular , Linhagem Celular Tumoral , Quimiocinas/metabolismo , Estudos de Coortes , Neoplasias Colorretais/genética , Reparo de Erro de Pareamento de DNA/genética , Células Endoteliais/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Imunidade , Inflamação/patologia , Monócitos/patologia , Células Mieloides/patologia , Neutrófilos/patologia , Células Estromais/metabolismo , Linfócitos T/metabolismo , Transcrição Gênica
2.
Cell ; 175(4): 984-997.e24, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30388455

RESUMO

Immune checkpoint inhibitors (ICIs) produce durable responses in some melanoma patients, but many patients derive no clinical benefit, and the molecular underpinnings of such resistance remain elusive. Here, we leveraged single-cell RNA sequencing (scRNA-seq) from 33 melanoma tumors and computational analyses to interrogate malignant cell states that promote immune evasion. We identified a resistance program expressed by malignant cells that is associated with T cell exclusion and immune evasion. The program is expressed prior to immunotherapy, characterizes cold niches in situ, and predicts clinical responses to anti-PD-1 therapy in an independent cohort of 112 melanoma patients. CDK4/6-inhibition represses this program in individual malignant cells, induces senescence, and reduces melanoma tumor outgrowth in mouse models in vivo when given in combination with immunotherapy. Our study provides a high-resolution landscape of ICI-resistant cell states, identifies clinically predictive signatures, and suggests new therapeutic strategies to overcome immunotherapy resistance.


Assuntos
Antineoplásicos/uso terapêutico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Melanoma/imunologia , Inibidores de Proteínas Quinases/uso terapêutico , Linfócitos T/imunologia , Evasão Tumoral , Idoso , Idoso de 80 Anos ou mais , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Feminino , Humanos , Imunoterapia/métodos , Masculino , Melanoma/tratamento farmacológico , Melanoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia
3.
Nucleic Acids Res ; 43(22): 10655-72, 2015 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-26578579

RESUMO

To understand how transposon landscapes (TLs) vary across animal genomes, we describe a new method called the Transposon Insertion and Depletion AnaLyzer (TIDAL) and a database of >300 TLs in Drosophila melanogaster (TIDAL-Fly). Our analysis reveals pervasive TL diversity across cell lines and fly strains, even for identically named sub-strains from different laboratories such as the ISO1 strain used for the reference genome sequence. On average, >500 novel insertions exist in every lab strain, inbred strains of the Drosophila Genetic Reference Panel (DGRP), and fly isolates in the Drosophila Genome Nexus (DGN). A minority (<25%) of transposon families comprise the majority (>70%) of TL diversity across fly strains. A sharp contrast between insertion and depletion patterns indicates that many transposons are unique to the ISO1 reference genome sequence. Although TL diversity from fly strains reaches asymptotic limits with increasing sequencing depth, rampant TL diversity causes unsaturated detection of TLs in pools of flies. Finally, we show novel transposon insertions negatively correlate with Piwi-interacting RNA (piRNA) levels for most transposon families, except for the highly-abundant roo retrotransposon. Our study provides a useful resource for Drosophila geneticists to understand how transposons create extensive genomic diversity in fly cell lines and strains.


Assuntos
Elementos de DNA Transponíveis , Drosophila melanogaster/genética , Genômica/métodos , Retroelementos , Animais , Linhagem Celular , Bases de Dados de Ácidos Nucleicos , Variação Genética , Genoma de Inseto , RNA Interferente Pequeno/metabolismo
4.
Cancer Cell ; 39(5): 649-661.e5, 2021 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-33711272

RESUMO

Immune checkpoint blockade (ICB) results in durable disease control in a subset of patients with advanced renal cell carcinoma (RCC), but mechanisms driving resistance are poorly understood. We characterize the single-cell transcriptomes of cancer and immune cells from metastatic RCC patients before or after ICB exposure. In responders, subsets of cytotoxic T cells express higher levels of co-inhibitory receptors and effector molecules. Macrophages from treated biopsies shift toward pro-inflammatory states in response to an interferon-rich microenvironment but also upregulate immunosuppressive markers. In cancer cells, we identify bifurcation into two subpopulations differing in angiogenic signaling and upregulation of immunosuppressive programs after ICB. Expression signatures for cancer cell subpopulations and immune evasion are associated with PBRM1 mutation and survival in primary and ICB-treated advanced RCC. Our findings demonstrate that ICB remodels the RCC microenvironment and modifies the interplay between cancer and immune cell populations critical for understanding response and resistance to ICB.


Assuntos
Carcinoma de Células Renais/terapia , Fatores Imunológicos/imunologia , Imunoterapia , Neoplasias Renais/terapia , Microambiente Tumoral/imunologia , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/patologia , Proteínas de Ligação a DNA/imunologia , Humanos , Imunoterapia/métodos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Fatores de Transcrição/imunologia
5.
Nat Med ; 27(3): 426-433, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33664492

RESUMO

Metastatic castration-resistant prostate cancer is typically lethal, exhibiting intrinsic or acquired resistance to second-generation androgen-targeting therapies and minimal response to immune checkpoint inhibitors1. Cellular programs driving resistance in both cancer and immune cells remain poorly understood. We present single-cell transcriptomes from 14 patients with advanced prostate cancer, spanning all common metastatic sites. Irrespective of treatment exposure, adenocarcinoma cells pervasively coexpressed multiple androgen receptor isoforms, including truncated isoforms hypothesized to mediate resistance to androgen-targeting therapies2,3. Resistance to enzalutamide was associated with cancer cell-intrinsic epithelial-mesenchymal transition and transforming growth factor-ß signaling. Small cell carcinoma cells exhibited divergent expression programs driven by transcriptional regulators promoting lineage plasticity and HOXB5, HOXB6 and NR1D2 (refs. 4-6). Additionally, a subset of patients had high expression of dysfunction markers on cytotoxic CD8+ T cells undergoing clonal expansion following enzalutamide treatment. Collectively, the transcriptional characterization of cancer and immune cells from human metastatic castration-resistant prostate cancer provides a basis for the development of therapeutic approaches complementing androgen signaling inhibition.


Assuntos
Antineoplásicos/farmacologia , Neoplasias de Próstata Resistentes à Castração/terapia , Transcrição Gênica/efeitos dos fármacos , Biópsia , Linfócitos T CD8-Positivos/imunologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/imunologia , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo
6.
Nat Med ; 26(8): 1271-1279, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32572264

RESUMO

Malignant abdominal fluid (ascites) frequently develops in women with advanced high-grade serous ovarian cancer (HGSOC) and is associated with drug resistance and a poor prognosis1. To comprehensively characterize the HGSOC ascites ecosystem, we used single-cell RNA sequencing to profile ~11,000 cells from 22 ascites specimens from 11 patients with HGSOC. We found significant inter-patient variability in the composition and functional programs of ascites cells, including immunomodulatory fibroblast sub-populations and dichotomous macrophage populations. We found that the previously described immunoreactive and mesenchymal subtypes of HGSOC, which have prognostic implications, reflect the abundance of immune infiltrates and fibroblasts rather than distinct subsets of malignant cells2. Malignant cell variability was partly explained by heterogeneous copy number alteration patterns or expression of a stemness program. Malignant cells shared expression of inflammatory programs that were largely recapitulated in single-cell RNA sequencing of ~35,000 cells from additionally collected samples, including three ascites, two primary HGSOC tumors and three patient ascites-derived xenograft models. Inhibition of the JAK/STAT pathway, which was expressed in both malignant cells and cancer-associated fibroblasts, had potent anti-tumor activity in primary short-term cultures and patient-derived xenograft models. Our work contributes to resolving the HSGOC landscape3-5 and provides a resource for the development of novel therapeutic approaches.


Assuntos
Ascite/genética , Cistadenoma Seroso/genética , Neoplasias Ovarianas/genética , Análise de Célula Única , Ascite/patologia , Linhagem Celular Tumoral , Cistadenoma Seroso/patologia , Variações do Número de Cópias de DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fibroblastos/metabolismo , Regulação Neoplásica da Expressão Gênica , Xenoenxertos , Humanos , Janus Quinase 1/genética , Gradação de Tumores , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/patologia , Prognóstico , Fatores de Transcrição STAT/genética , Análise de Sequência de RNA , Transdução de Sinais/genética
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