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1.
Cell ; 187(1): 149-165.e23, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38134933

RESUMO

Deciphering the cell-state transitions underlying immune adaptation across time is fundamental for advancing biology. Empirical in vivo genomic technologies that capture cellular dynamics are currently lacking. We present Zman-seq, a single-cell technology recording transcriptomic dynamics across time by introducing time stamps into circulating immune cells, tracking them in tissues for days. Applying Zman-seq resolved cell-state and molecular trajectories of the dysfunctional immune microenvironment in glioblastoma. Within 24 hours of tumor infiltration, cytotoxic natural killer cells transitioned to a dysfunctional program regulated by TGFB1 signaling. Infiltrating monocytes differentiated into immunosuppressive macrophages, characterized by the upregulation of suppressive myeloid checkpoints Trem2, Il18bp, and Arg1, over 36 to 48 hours. Treatment with an antagonistic anti-TREM2 antibody reshaped the tumor microenvironment by redirecting the monocyte trajectory toward pro-inflammatory macrophages. Zman-seq is a broadly applicable technology, enabling empirical measurements of differentiation trajectories, which can enhance the development of more efficacious immunotherapies.


Assuntos
Glioblastoma , Humanos , Perfilação da Expressão Gênica , Glioblastoma/patologia , Imunoterapia , Células Matadoras Naturais , Macrófagos , Microambiente Tumoral , Análise de Célula Única
2.
Cancer Discov ; 13(12): 2610-2631, 2023 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-37756565

RESUMO

Cancer mortality primarily stems from metastatic recurrence, emphasizing the urgent need for developing effective metastasis-targeted immunotherapies. To better understand the cellular and molecular events shaping metastatic niches, we used a spontaneous breast cancer lung metastasis model to create a single-cell atlas spanning different metastatic stages and regions. We found that premetastatic lungs are infiltrated by inflammatory neutrophils and monocytes, followed by the accumulation of suppressive macrophages with the emergence of metastases. Spatial profiling revealed that metastasis-associated immune cells were present in the metastasis core, with the exception of TREM2+ regulatory macrophages uniquely enriched at the metastatic invasive margin, consistent across both murine models and human patient samples. These regulatory macrophages (Mreg) contribute to the formation of an immune-suppressive niche, cloaking tumor cells from immune surveillance. Our study provides a compendium of immune cell dynamics across metastatic stages and niches, informing the development of metastasis-targeting immunotherapies. SIGNIFICANCE: Temporal and spatial single-cell analysis of metastasis stages revealed new players in modulating immune surveillance and suppression. Our study highlights distinct populations of TREM2 macrophages as modulators of the microenvironment in metastasis, and as the key immune determinant defining metastatic niches, pointing to myeloid checkpoints to improve therapeutic strategies. This article is featured in Selected Articles from This Issue, p. 2489.


Assuntos
Neoplasias da Mama , Neoplasias Pulmonares , Camundongos , Humanos , Animais , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias Pulmonares/patologia , Pulmão/patologia , Macrófagos , Microambiente Tumoral , Metástase Neoplásica/patologia , Glicoproteínas de Membrana , Receptores Imunológicos
3.
Front Immunol ; 14: 1183578, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37359522

RESUMO

Immunotherapy has revolutionized cancer care in the past decade. Treatment with immune checkpoint inhibitors has demonstrated promising clinical activity against tumors. However, only a subset of patients responds to these treatments, limiting their potential benefit. Efforts to understand, predict, and overcome the lack of response in patients, have thus far focused mainly on the tumor immunogenicity and the quantity and characteristics of tumor-infiltrating T cells, since these cells are the main effectors of immunotherapies. However, recent comprehensive analyses of the tumor microenvironment (TME) in the context of immune checkpoint blockade (ICB) therapy have revealed critical functions of other immune cells in the effective anti-tumor response, highlighting the need to account for complex cell-cell interaction and communication underlying clinical outputs. In this perspective, I discuss the current understanding of the crucial roles of tumor-associated macrophages (TAMs) in the success of T cell-directed immune checkpoint blockade therapies, as well as the present, and the future of clinical trials on combinatorial therapies targeting both cell types.


Assuntos
Neoplasias , Linfócitos T , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Macrófagos Associados a Tumor/metabolismo , Neoplasias/patologia , Imunoterapia , Microambiente Tumoral
4.
Cell ; 182(4): 872-885.e19, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32783915

RESUMO

Cell function and activity are regulated through integration of signaling, epigenetic, transcriptional, and metabolic pathways. Here, we introduce INs-seq, an integrated technology for massively parallel recording of single-cell RNA sequencing (scRNA-seq) and intracellular protein activity. We demonstrate the broad utility of INs-seq for discovering new immune subsets by profiling different intracellular signatures of immune signaling, transcription factor combinations, and metabolic activity. Comprehensive mapping of Arginase 1-expressing cells within tumor models, a metabolic immune signature of suppressive activity, discovers novel Arg1+ Trem2+ regulatory myeloid (Mreg) cells and identifies markers, metabolic activity, and pathways associated with these cells. Genetic ablation of Trem2 in mice inhibits accumulation of intra-tumoral Mreg cells, leading to a marked decrease in dysfunctional CD8+ T cells and reduced tumor growth. This study establishes INs-seq as a broadly applicable technology for elucidating integrated transcriptional and intra-cellular maps and identifies the molecular signature of myeloid suppressive cells in tumors.


Assuntos
Glicoproteínas de Membrana/metabolismo , Neoplasias/patologia , RNA Citoplasmático Pequeno/química , Receptores Imunológicos/metabolismo , Animais , Arginase/genética , Arginase/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Células Dendríticas/citologia , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/metabolismo , Lipopolissacarídeos/farmacologia , Glicoproteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/metabolismo , RNA Citoplasmático Pequeno/metabolismo , Receptores Imunológicos/genética , Análise de Sequência de RNA , Análise de Célula Única , Fatores de Transcrição/metabolismo , Microambiente Tumoral , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno
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