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1.
Immunity ; 57(8): 1923-1938.e7, 2024 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-38878769

RESUMO

Fasting is associated with improved outcomes in cancer. Here, we investigated the impact of fasting on natural killer (NK) cell anti-tumor immunity. Cyclic fasting improved immunity against solid and metastatic tumors in an NK cell-dependent manner. During fasting, NK cells underwent redistribution from peripheral tissues to the bone marrow (BM). In humans, fasting also reduced circulating NK cell numbers. NK cells in the spleen of fasted mice were metabolically rewired by elevated concentrations of fatty acids and glucocorticoids, augmenting fatty acid metabolism via increased expression of the enzyme CPT1A, and Cpt1a deletion impaired NK cell survival and function in this setting. In parallel, redistribution of NK cells to the BM during fasting required the trafficking mediators S1PR5 and CXCR4. These cells were primed by an increased pool of interleukin (IL)-12-expressing BM myeloid cells, which improved IFN-γ production. Our findings identify a link between dietary restriction and optimized innate immune responses, with the potential to enhance immunotherapy strategies.


Assuntos
Jejum , Células Matadoras Naturais , Camundongos Endogâmicos C57BL , Animais , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Camundongos , Humanos , Neoplasias/imunologia , Medula Óssea/imunologia , Medula Óssea/metabolismo , Camundongos Knockout , Interferon gama/metabolismo , Interferon gama/imunologia , Baço/imunologia , Baço/metabolismo , Imunidade Inata/imunologia , Interleucina-12/metabolismo , Interleucina-12/imunologia , Receptores CXCR4/metabolismo
2.
Proc Natl Acad Sci U S A ; 121(11): e2319254121, 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442180

RESUMO

Natural killer (NK) cells are a vital part of the innate immune system capable of rapidly clearing mutated or infected cells from the body and promoting an immune response. Here, we find that NK cells activated by viral infection or tumor challenge increase uptake of fatty acids and their expression of carnitine palmitoyltransferase I (CPT1A), a critical enzyme for long-chain fatty acid oxidation. Using a mouse model with an NK cell-specific deletion of CPT1A, combined with stable 13C isotope tracing, we observe reduced mitochondrial function and fatty acid-derived aspartate production in CPT1A-deficient NK cells. Furthermore, CPT1A-deficient NK cells show reduced proliferation after viral infection and diminished protection against cancer due to impaired actin cytoskeleton rearrangement. Together, our findings highlight that fatty acid oxidation promotes NK cell metabolic resilience, processes that can be optimized in NK cell-based immunotherapies.


Assuntos
Neoplasias , Viroses , Humanos , Metabolismo dos Lipídeos , Células Matadoras Naturais , Ácidos Graxos
3.
BMC Cancer ; 20(1): 542, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522170

RESUMO

BACKGROUND: Novel biomarkers are required to discern between breast tumors that should be targeted for treatment from those that would never become clinically apparent and/or life threatening for patients. Moreover, therapeutics that specifically target breast cancer (BC) cells with tumor-initiating capacity to prevent recurrence are an unmet need. We investigated the clinical importance of LGR5 in BC and ductal carcinoma in situ (DCIS) to explore LGR5 as a biomarker and a therapeutic target. METHODS: We stained BC (n = 401) and DCIS (n = 119) tissue microarrays with an antibody against LGR5. We examined an LGR5 knockdown ER- cell line that was orthotopically transplanted and used for in vitro colony assays. We also determined the tumor-initiating role of Lgr5 in lineage-tracing experiments. Lastly, we transplanted ER- patient-derived xenografts into mice that were subsequently treated with a LGR5 antibody drug conjugate (anti-LGR5-ADC). RESULTS: LGR5 expression correlated with small tumor size, lower grade, lymph node negativity, and ER-positivity. ER+ patients with LGR5high tumors rarely had recurrence, while high-grade ER- patients with LGR5high expression recurred and died due to BC more often. Intriguingly, all the DCIS patients who later died of BC had LGR5-positive tumors. Colony assays and xenograft experiments substantiated a role for LGR5 in ER- tumor initiation and subsequent growth, which was further validated by lineage-tracing experiments in ER- /triple-negative BC mouse models. Importantly, by utilizing LGR5high patient-derived xenografts, we showed that anti-LGR5-ADC should be considered as a therapeutic for high-grade ER- BC. CONCLUSION: LGR5 has distinct roles in ER- vs. ER+ BC with potential clinical applicability as a biomarker to identify patients in need of therapy and could serve as a therapeutic target for high-grade ER- BC.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Carcinoma Intraductal não Infiltrante/química , Receptores Acoplados a Proteínas G/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/diagnóstico , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos , Pessoa de Meia-Idade , Prognóstico , RNA Neoplásico/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/análise , Receptores Acoplados a Proteínas G/imunologia , Análise Serial de Tecidos/métodos
4.
Drug Resist Updat ; 33-35: 23-35, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-29145972

RESUMO

The advent of cancer immunotherapy (CIT) and its success in treating primary and metastatic cancer may offer substantially improved outcomes for patients. Despite recent advancements, many malignancies remain resistant to CIT, among which are brain metastases, a particularly virulent disease with no apparent cure. The immunologically unique niche of the brain has prompted compelling new questions in immuno-oncology such as the effects of tissue-specific differences in immune response, heterogeneity between primary tumors and distant metastases, and the role of spatiotemporal dynamics in shaping an effective anti-tumor immune response. Current methods to examine the immunobiology of metastases in the brain are constrained by tissue processing methods that limit spatial data collection, omit dynamic information, and cannot recapitulate the heterogeneity of the tumor microenvironment. In the current review, we describe how high-resolution, live imaging tools, particularly intravital microscopy (IVM), are instrumental in answering these questions. IVM of pre-clinical cancer models enables short- and long-term observations of critical immunobiology and metastatic growth phenomena to potentially generate revolutionary insights into the spatiotemporal dynamics of brain metastasis, interactions of CIT with immune elements therein, and influence of chemo- and radiotherapy. We describe the utility of IVM to study brain metastasis in mice by tracking the migration and growth of fluorescently-labeled cells, including cancer cells and immune subsets, while monitoring the physical environment within optical windows using imaging dyes and other signal generation mechanisms to illuminate angiogenesis, hypoxia, and/or CIT drug expression within the metastatic niche. Our review summarizes the current knowledge regarding brain metastases and the immune milieu, presents the current status of CIT and its prospects in targeting brain metastases to circumvent therapeutic resistance, and proposes avenues to utilize IVM to study CIT drug delivery and therapeutic efficacy in preclinical models that will ultimately facilitate novel drug discovery and innovative combination therapies.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Neoplasias Encefálicas/terapia , Resistencia a Medicamentos Antineoplásicos , Imunoterapia/métodos , Oncologia/métodos , Animais , Antineoplásicos Imunológicos/uso terapêutico , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Neoplasias Encefálicas/diagnóstico por imagem , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/secundário , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/tendências , Humanos , Microscopia Intravital , Oncologia/tendências , Camundongos , Resultado do Tratamento , Microambiente Tumoral/imunologia
5.
bioRxiv ; 2023 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-37986752

RESUMO

Natural Killer (NK) cells are innate cytotoxic lymphocytes that possess features of adaptive immunity, including antigen specificity and clonal expansion. NK cells rapidly respond to cytokines released during the innate phase of viral infection and are thought to migrate from circulation into infected organs to execute their early effector functions. However, recent evidence suggests that tissue-resident NK cells are among the first responders to viral infection. In this study, we observe that antigen receptor signaling precedes substantial proinflammatory cytokine signaling in a population of NK cells during mouse cytomegalovirus infection. Early antigen receptor signals epigenetically prime NK cells for optimal expansion during the later adaptive phase of the antiviral response. Mechanistically, receptor signaling increases chromatin accessibility at STAT4-binding genomic sites within differentiating NK cells. To promote adaptive programming of NK cells during infection, activating receptor-dependent epigenetic remodeling antagonizes IL-12 driven terminal maturation, poises NK cells for proliferation via sustained CDK6 expression, and antagonizes early apoptosis of short-lived effector cells via suppression of Bim. Thus, antigen receptor signaling alters an IL-12 dependent fate decision during the innate-to-adaptive transition of antiviral NK cells.

6.
Nat Commun ; 14(1): 5945, 2023 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-37741832

RESUMO

Microsatellite-stable colorectal cancer (MSS-CRC) is highly refractory to immunotherapy. Understanding tumor-intrinsic determinants of immunotherapy resistance is critical to improve MSS-CRC patient outcomes. Here, we demonstrate that high tumor expression of the core autophagy gene ATG16L1 is associated with poor clinical response to anti-PD-L1 therapy in KRAS-mutant tumors from IMblaze370 (NCT02788279), a large phase III clinical trial of atezolizumab (anti-PD-L1) in advanced metastatic MSS-CRC. Deletion of Atg16l1 in engineered murine colon cancer organoids inhibits tumor growth in primary (colon) and metastatic (liver and lung) niches in syngeneic female hosts, primarily due to increased sensitivity to IFN-γ-mediated immune pressure. ATG16L1 deficiency enhances programmed cell death of colon cancer organoids induced by IFN-γ and TNF, thus increasing their sensitivity to host immunity. In parallel, ATG16L1 deficiency reduces tumor stem-like populations in vivo independently of adaptive immune pressure. This work reveals autophagy as a clinically relevant mechanism of immune evasion and tumor fitness in MSS-CRC and provides a rationale for autophagy inhibition to boost immunotherapy responses in the clinic.


Assuntos
Neoplasias do Colo , Neoplasias Colorretais , Animais , Feminino , Humanos , Camundongos , Autofagia/genética , Proteínas Relacionadas à Autofagia/genética , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Genes Reguladores , Fígado , Ensaios Clínicos Fase III como Assunto
7.
Life Sci Alliance ; 2(6)2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31727800

RESUMO

Metastasis, the main cause of cancer-related death, has traditionally been viewed as a late-occurring process during cancer progression. Using the MMTV-PyMT luminal B breast cancer model, we demonstrate that the lung metastatic niche is established early during tumorigenesis. We found that matrix metalloproteinase 9 (MMP9) is an important component of the metastatic niche early in tumorigenesis and promotes circulating tumor cells to colonize the lungs. Blocking active MMP9, using a monoclonal antibody specific to the active form of gelatinases, inhibited endogenous and experimental lung metastases in the MMTV-PyMT model. Mechanistically, inhibiting MMP9 attenuated migration, invasion, and colony formation and promoted CD8+ T cell infiltration and activation. Interestingly, primary tumor burden was unaffected, suggesting that inhibiting active MMP9 is primarily effective during the early metastatic cascade. These findings suggest that the early metastatic circuit can be disrupted by inhibiting active MMP9 and warrant further studies of MMP9-targeted anti-metastatic breast cancer therapy.


Assuntos
Neoplasias da Mama/enzimologia , Neoplasias Mamárias Experimentais/enzimologia , Metaloproteinase 9 da Matriz/metabolismo , Animais , Anticorpos/imunologia , Anticorpos/farmacologia , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinogênese , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/secundário , Neoplasias Mamárias Experimentais/imunologia , Neoplasias Mamárias Experimentais/patologia , Metaloproteinase 9 da Matriz/imunologia , Inibidores de Metaloproteinases de Matriz/farmacologia , Camundongos , Camundongos Endogâmicos , Invasividade Neoplásica , Metástase Neoplásica
8.
Front Cell Dev Biol ; 6: 19, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29546043

RESUMO

There is a growing list of cancer immunotherapeutics approved for use in a population with an increasing number of aged individuals. Cancer immunotherapy (CIT) mediates tumor destruction by activating anti-tumor immune responses that have been silenced through the oncogenic process. However, in an aging individual, immune deregulation is positively correlated with age. In this context, it is vital to examine the age-related changes in the tumor microenvironment (TME) and specifically, those directly affecting critical players to ensure CIT efficacy. Effector T cells, regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and tumor-associated neutrophils play important roles in promoting or inhibiting the inflammatory response, while cancer-associated fibroblasts are key mediators of the extracellular matrix (ECM). Immune checkpoint inhibitors function optimally in inflamed tumors heavily invaded by CD4 and CD8 T cells. However, immunosenescence curtails the effector T cell response within the TME and causes ECM deregulation, creating a biophysical barrier impeding both effective drug delivery and pro-inflammatory responses. The ability of the chimeric antigen receptor T (CAR-T) cell to artificially induce an adaptive immune response can be modified to degrade essential components of the ECM and alleviate the age-related changes to the TME. This review will focus on the age-related alterations in ECM and immune-stroma interactions within the TME. We will discuss strategies to overcome the barriers of immunosenescence and matrix deregulation to ameliorate the efficacy of CIT in aged subjects.

9.
Oncotarget ; 9(13): 10945-10961, 2018 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-29541388

RESUMO

Tumor endothelial cells (TEC) play an indispensible role in tumor growth and metastasis although much of the detailed mechanism still remains elusive. In this study we characterized and compared the global gene expression profiles of TECs and control ECs isolated from human breast cancerous tissues and reduction mammoplasty tissues respectively by single cell RNA sequencing (scRNA-seq). Based on the qualified scRNA-seq libraries that we made, we found that 1302 genes were differentially expressed between these two EC phenotypes. Both principal component analysis (PCA) and heat map-based hierarchical clustering separated the cancerous versus control ECs as two distinctive clusters, and MetaCore disease biomarker analysis indicated that these differentially expressed genes are highly correlated with breast neoplasm diseases. Gene Set Enrichment Analysis software (GSEA) enriched these genes to extracellular matrix (ECM) signal pathways and highlighted 127 ECM-associated genes. External validation verified some of these ECM-associated genes are not only generally overexpressed in various cancer tissues but also specifically overexpressed in colorectal cancer ECs and lymphoma ECs. In conclusion, our data demonstrated that ECM-associated genes play pivotal roles in breast cancer EC biology and some of them could serve as potential TEC biomarkers for various cancers.

10.
Oncotarget ; 7(48): 79262-79273, 2016 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-27813493

RESUMO

Mesenchymal stem cells-derived fibroblasts (MSC-DF) constitute a significant portion of stromal fibroblasts in the tumor microenvironment (TME) and are key modulators of tumor progression. However, the molecular mechanisms that determine their tumor-regulatory function are poorly understood. Here, we uncover the Notch1 pathway as a molecular determinant that selectively controls the regulatory role of MSC-DF in melanoma metastasis. We demonstrate that the Notch1 pathway's activity is inversely correlated with the metastasis-regulating function of fibroblasts and can determine the metastasis-promoting or -suppressing phenotype of MSC-DF. When co-grafted with melanoma cells, MSC-DFNotch1-/- selectively promote, while MSC-DFN1IC+/+ preferentially suppress melanoma metastasis, but not growth, in mouse models. Consistently, conditioned media (CM) from MSC-DFNotch1-/- and MSC-DFN1IC+/+ oppositely, yet selectively regulates migration, but not growth of melanoma cells in vitro. Additionally, when co-cultured with metastatic melanoma cells in vitro, MSC-DFNotch1-/- support, while MSC-DFN1IC+/+ inhibit melanoma cells in the formation of spheroids. These findings expand the repertoire of Notch1 signaling as a molecular switch in determining the tumor metastasis-regulating function of MSC-DF. We also identified Wnt-induced secreted protein-1 (WISP-1) as a key downstream secretory mediator of Notch1 signaling to execute the influential role of MSC-DF on melanoma metastasis. These findings reveal the Notch1-WISP-1 axis as a crucial molecular determinant in governing stromal regulation of melanoma metastasis; thus, establishing this axis as a potential therapeutic target for melanoma metastasis.


Assuntos
Proteínas de Sinalização Intercelular CCN/metabolismo , Fibroblastos/citologia , Melanoma/patologia , Células-Tronco Mesenquimais/citologia , Proteínas Proto-Oncogênicas/metabolismo , Receptor Notch1/genética , Animais , Linhagem Celular Tumoral , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Fibroblastos/patologia , Humanos , Melanoma/genética , Melanoma/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Metástase Neoplásica , Receptor Notch1/metabolismo , Transdução de Sinais , Microambiente Tumoral
11.
J Pediatr Surg ; 51(6): 1047-50, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27342010

RESUMO

Kaposiform hemangioendothelioma is a rare locally aggressive vascular tumor that usually manifests during early childhood. Typically the lesion presents with skin, soft tissue and bone involvement and is characterized histologically by ill-defined nodularity and the presence of spindle cells with resemblance to Kaposi's sarcoma. We report a rare neonatal case of a splenic kaposiform hemangioendothelioma associated with Kasabach-Merritt phenomenon that was diagnosed with radiographic imaging. Because of the rapid onset of thrombocytopenia and anemia, the patient required urgent splenectomy with subsequent resolution of the blood dyscrasias.


Assuntos
Hemangioendotelioma/diagnóstico , Síndrome de Kasabach-Merritt/diagnóstico , Sarcoma de Kaposi/diagnóstico , Baço/diagnóstico por imagem , Neoplasias Esplênicas/diagnóstico , Diagnóstico Diferencial , Hemangioendotelioma/cirurgia , Humanos , Recém-Nascido , Síndrome de Kasabach-Merritt/cirurgia , Imageamento por Ressonância Magnética , Masculino , Radiografia , Sarcoma de Kaposi/cirurgia , Esplenectomia , Neoplasias Esplênicas/cirurgia
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