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1.
Immunity ; 54(10): 2338-2353.e6, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34534439

RESUMO

In tumors, a subset of CD8+ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1+ CD8+ T cells revealed that while intratumoral TCF-1+ CD8+ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1+ CD8+ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1+ CD8+ T cell subsets developed over time-a proliferative SlamF6+ subset and a non-cycling SlamF6- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1+ CD8+ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6+ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1+ CD8+ T cells and their decrease contributes to failed anti-tumor immunity.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Linfócitos T CD8-Positivos/imunologia , Células Dendríticas/imunologia , Neoplasias Pulmonares/imunologia , Linfonodos/imunologia , Fator 1 de Transcrição de Linfócitos T/imunologia , Animais , Camundongos , Subpopulações de Linfócitos T/imunologia
2.
Cancer Discov ; 12(2): 562-585, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34561242

RESUMO

SMARCA4/BRG1 encodes for one of two mutually exclusive ATPases present in mammalian SWI/SNF chromatin remodeling complexes and is frequently mutated in human lung adenocarcinoma. However, the functional consequences of SMARCA4 mutation on tumor initiation, progression, and chromatin regulation in lung cancer remain poorly understood. Here, we demonstrate that loss of Smarca4 sensitizes club cell secretory protein-positive cells within the lung in a cell type-dependent fashion to malignant transformation and tumor progression, resulting in highly advanced dedifferentiated tumors and increased metastatic incidence. Consistent with these phenotypes, Smarca4-deficient primary tumors lack lung lineage transcription factor activities and resemble a metastatic cell state. Mechanistically, we show that Smarca4 loss impairs the function of all three classes of SWI/SNF complexes, resulting in decreased chromatin accessibility at lung lineage motifs and ultimately accelerating tumor progression. Thus, we propose that the SWI/SNF complex via Smarca4 acts as a gatekeeper for lineage-specific cellular transformation and metastasis during lung cancer evolution. SIGNIFICANCE: We demonstrate cell-type specificity in the tumor-suppressive functions of SMARCA4 in the lung, pointing toward a critical role of the cell-of-origin in driving SWI/SNF-mutant lung adenocarcinoma. We further show the direct effects of SMARCA4 loss on SWI/SNF function and chromatin regulation that cause aggressive malignancy during lung cancer evolution.This article is highlighted in the In This Issue feature, p. 275.


Assuntos
Adenocarcinoma de Pulmão/genética , Transformação Celular Neoplásica , DNA Helicases/genética , Neoplasias Pulmonares/genética , Metástase Neoplásica , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Adenocarcinoma de Pulmão/secundário , Animais , Modelos Animais de Doenças , Humanos , Neoplasias Pulmonares/patologia , Camundongos
3.
Cancer Res ; 80(18): 3841-3854, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32690724

RESUMO

Inactivation of SMARCA4/BRG1, the core ATPase subunit of mammalian SWI/SNF complexes, occurs at very high frequencies in non-small cell lung cancers (NSCLC). There are no targeted therapies for this subset of lung cancers, nor is it known how mutations in BRG1 contribute to lung cancer progression. Using a combination of gain- and loss-of-function approaches, we demonstrate that deletion of BRG1 in lung cancer leads to activation of replication stress responses. Single-molecule assessment of replication fork dynamics in BRG1-deficient cells revealed increased origin firing mediated by the prelicensing protein, CDC6. Quantitative mass spectrometry and coimmunoprecipitation assays showed that BRG1-containing SWI/SNF complexes interact with RPA complexes. Finally, BRG1-deficient lung cancers were sensitive to pharmacologic inhibition of ATR. These findings provide novel mechanistic insight into BRG1-mutant lung cancers and suggest that their dependency on ATR can be leveraged therapeutically and potentially expanded to BRG1-mutant cancers in other tissues. SIGNIFICANCE: These findings indicate that inhibition of ATR is a promising therapy for the 10% of non-small cell lung cancer patients harboring mutations in SMARCA4/BRG1. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/18/3841/F1.large.jpg.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/genética , DNA Helicases/genética , Deleção de Genes , Neoplasias Pulmonares/genética , Proteínas Nucleares/genética , Fatores de Transcrição/genética , Animais , Proteínas de Ciclo Celular/metabolismo , Proteínas Cromossômicas não Histona , DNA Helicases/deficiência , Progressão da Doença , Feminino , Fatores de Transcrição Forkhead , Edição de Genes , Humanos , Imunoprecipitação , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Proteínas Nucleares/deficiência , Proteínas Nucleares/metabolismo , Análise de Sequência de RNA , Fatores de Transcrição/deficiência
4.
Cancer Cell ; 38(2): 229-246.e13, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32707077

RESUMO

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS.


Assuntos
Plasticidade Celular/genética , Células Epiteliais/metabolismo , Transição Epitelial-Mesenquimal/genética , Neoplasias Pulmonares/genética , Células-Tronco Neoplásicas/metabolismo , Animais , Diferenciação Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Células Cultivadas , Modelos Animais de Doenças , Células Epiteliais/citologia , Heterogeneidade Genética , Humanos , Neoplasias Pulmonares/patologia , Camundongos , Análise de Célula Única/métodos , Transcriptoma/genética
5.
Cell Rep ; 29(10): 2998-3008.e8, 2019 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-31801068

RESUMO

Regulatory T cells (Tregs) can impair anti-tumor immune responses and are associated with poor prognosis in multiple cancer types. Tregs in human tumors span diverse transcriptional states distinct from those of peripheral Tregs, but their contribution to tumor development remains unknown. Here, we use single-cell RNA sequencing (RNA-seq) to longitudinally profile dynamic shifts in the distribution of Tregs in a genetically engineered mouse model of lung adenocarcinoma. In this model, interferon-responsive Tregs are more prevalent early in tumor development, whereas a specialized effector phenotype characterized by enhanced expression of the interleukin-33 receptor ST2 is predominant in advanced disease. Treg-specific deletion of ST2 alters the evolution of effector Treg diversity, increases infiltration of CD8+ T cells into tumors, and decreases tumor burden. Our study shows that ST2 plays a critical role in Treg-mediated immunosuppression in cancer, highlighting potential paths for therapeutic intervention.


Assuntos
Interleucina-33/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD8-Positivos/imunologia , Feminino , Tolerância Imunológica/imunologia , Terapia de Imunossupressão/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Microambiente Tumoral/imunologia
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