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1.
Gut ; 70(1): 127-138, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32424005

RESUMO

OBJECTIVE: This study exploits the intersection between molecular-targeted therapies and immune-checkpoint inhibition to define new means to treat pancreatic cancer. DESIGN: Patient-derived cell lines and xenograft models were used to define the response to CDK4/6 and MEK inhibition in the tumour compartment. Impacts relative to immunotherapy were performed using subcutaneous and orthotopic syngeneic models. Single-cell RNA sequencing and multispectral imaging were employed to delineate effects on the immunological milieu in the tumour microenvironment. RESULTS: We found that combination treatment with MEK and CDK4/6 inhibitors was effective across a broad range of PDX models in delaying tumour progression. These effects were associated with stable cell-cycle arrest, as well as the induction of multiple genes associated with interferon response and antigen presentation in an RB-dependent fashion. Using single-cell sequencing and complementary approaches, we found that the combination of CDK4/6 and MEK inhibition had a significant impact on increasing T-cell infiltration and altering myeloid populations, while potently cooperating with immune checkpoint inhibitors. CONCLUSIONS: Together, these data indicate that there are canonical and non-canonical features of CDK4/6 and MEK inhibition that impact on the tumour and immune microenvironment. This combination-targeted treatment can promote robust tumour control in combination with immune checkpoint inhibitor therapy.


Assuntos
Carcinoma Ductal Pancreático/terapia , Inibidores de Checkpoint Imunológico/uso terapêutico , Terapia de Alvo Molecular , Neoplasias Pancreáticas/terapia , Animais , Técnicas de Cultura de Células , Pontos de Checagem do Ciclo Celular , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Modelos Animais de Doenças , Humanos , Camundongos , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Mol Cancer Ther ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39148328

RESUMO

The combination of CDK4/6 and MEK inhibition as a therapeutic strategy has shown promise in various cancer models, particularly in those harboring RAS mutations. An initial high-throughput drug screen identified a high synergy between the CDK4/6 inhibitor palbociclib and the MEK inhibitor trametinib when used in combination in soft tissue sarcomas. In RAS mutant models, combination treatment with palbociclib and trametinib induced significant G1 cell cycle arrest, resulting in a marked reduction in cell proliferation and growth. CRISPR-mediated RB1 depletion resulted in a decreased response to CDK4/6 and MEK inhibition, which was validated in both cell culture and xenograft models. Beyond its cell cycle inhibitory effects, pathway enrichment analysis revealed the robust activation of interferon pathways upon CDK4/6 and MEK inhibition. This induction of gene expression was associated with the upregulation of retroviral elements. The TBK1(TANK-binding kinase 1) inhibitor GSK8612 selectively blocked the induction of interferon-related genes induced by palbociclib and trametinib treatment, and highlighted the separable epigenetic responses elicited by combined CDK4/6 and MEK inhibition. Together, these findings provide key mechanistic insights into the therapeutic potential of CDK4/6 and MEK inhibition in soft tissue sarcoma.

3.
iScience ; 27(3): 109187, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38420590

RESUMO

Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity.

4.
JCI Insight ; 8(8)2023 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-37092550

RESUMO

The main cause of malignancy-related mortality is metastasis. Although metastatic progression is driven by diverse tumor-intrinsic mechanisms, there is a growing appreciation for the contribution of tumor-extrinsic elements of the tumor microenvironment, especially macrophages, which correlate with poor clinical outcomes. Macrophages consist of bone marrow-derived and tissue-resident populations. In contrast to bone marrow-derived macrophages, the transcriptional pathways that govern the pro-metastatic activities of tissue-resident macrophages (TRMs) remain less clear. Alveolar macrophages (AMs) are a TRM population with critical roles in tissue homeostasis and metastasis. Wnt/ß-catenin signaling is a hallmark of cancer and has been identified as a pathologic regulator of AMs in infection. We tested the hypothesis that ß-catenin expression in AMs enhances metastasis in solid tumor models. Using a genetic ß-catenin gain-of-function approach, we demonstrated that (a) enhanced ß-catenin in AMs heightened lung metastasis; (b) ß-catenin activity in AMs drove a dysregulated inflammatory program strongly associated with Tnf expression; and (c) localized TNF-α blockade abrogated this metastatic outcome. Last, ß-catenin gene CTNNB1 and TNF expression levels were positively correlated in AMs of patients with lung cancer. Overall, our findings revealed a Wnt/ß-catenin/TNF-α pro-metastatic axis in AMs with potential therapeutic implications against tumors refractory to the antineoplastic actions of TNF-α.


Assuntos
Neoplasias Pulmonares , Macrófagos Alveolares , Humanos , Macrófagos Alveolares/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Pulmonares/patologia , Via de Sinalização Wnt , Microambiente Tumoral
5.
Cancer Cell ; 39(6): 734-737, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-33798473

RESUMO

Macrophages are multi-functional innate immune cells that occupy normal or pathologic tissues, including cancer tissues. The importance of macrophage ontogeny and the transcriptional networks underlying their functional diversity are underappreciated in immuno-oncology. Here, we discuss the implications of these fundamental characteristics for therapeutically reprogramming macrophages to sustain their tumoricidal activities.


Assuntos
Macrófagos/imunologia , Neoplasias/terapia , Microambiente Tumoral/fisiologia , Animais , Células da Medula Óssea , Citotoxicidade Imunológica , Humanos , Macrófagos/fisiologia , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Neoplasias/patologia
6.
Mol Immunol ; 118: 165-173, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31884388

RESUMO

The adaptive immune system is essential for host defense against pathogenic challenges, and a major constituent is the CD8+ cytotoxic T cell. Ordinarily, CD8+ T cells are endowed with a unique ability to specifically recognize and destroy their targets. However, in cases where disease emerges, especially in cancer, the efficacy of the CD8+ T cell response is frequently counterbalanced in a 'tug-of-war' by networks of tumor-driven mechanisms of immune suppression. As a result, antitumor CD8+ T cell activity is hampered, which contributes to clinical manifestations of disease. It is now well-recognized that prominent elements of that network include myeloid-derived suppressor cells (MDSC) and macrophages which assume tumor-supportive phenotypes. Both myeloid populations are thought to arise as consequences of chronic inflammatory cues produced during the neoplastic process. Numerous preclinical studies have now shown that inhibiting the production, trafficking and/or function of these immune suppressive myeloid populations restore antitumor CD8+ T cell responses during both immune surveillance or in response to immune-targeted interventions. Correlative studies in cancer patients support these preclinical findings and, thus, have laid the foundation for ongoing clinical trials in patients receiving novel agents that target such myeloid elements alone or in combination with immunotherapy to potentially improve cancer patient outcomes. Accordingly, this review focuses on how and why it is important to study the myeloid-T cell interplay as an innovative strategy to boost or reinvigorate the CD8+ T cell response as a critical weapon in the battle against malignancy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Células Mieloides/imunologia , Neoplasias/imunologia , Neoplasias/terapia , Animais , Humanos , Imunoterapia/métodos , Linfócitos T Citotóxicos/imunologia
7.
Leukemia ; 34(9): 2460-2472, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32099035

RESUMO

The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu. In solid tumors, CD141Hi conventional dendritic cells (CD141Hi cDCs) are necessary for antitumor immunosurveillance and the response to immunotherapy. Here, we found that CD141Hi cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141Hi cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141Hi cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141Hi cDCs, we found fewer numbers of progenitors committed to DC differentiation in the MDS bone marrow and these progenitors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141Hi cDC differentiation. To rescue impaired CD141Hi cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141Hi cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu. Epigenetic regulation of CD141Hi cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.


Assuntos
Antígenos de Superfície/imunologia , Diferenciação Celular , Células Dendríticas/citologia , Histona Desmetilases/antagonistas & inibidores , Síndromes Mielodisplásicas/patologia , Células-Tronco Neoplásicas/patologia , Animais , Diferenciação Celular/genética , Células Dendríticas/imunologia , Epigênese Genética , Feminino , Histona Desmetilases/metabolismo , Humanos , Fatores Reguladores de Interferon/metabolismo , Camundongos , Camundongos Knockout , Células-Tronco Neoplásicas/metabolismo , Trombomodulina
8.
Exp Clin Transplant ; 14(4): 377-84, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27267780

RESUMO

BK virus nephropathy is a challenging clinical problem in kidney transplant recipients with wide range of surveillance and management practices, based on individual experience. BK virus reactivation in kidney transplant recipients can result in BK virus nephropathy and graft loss. The most effective strategy for early diagnosis and treatment of BK virus nephropathy is regular monitoring for BK virus, currently achieved by quantification of viral DNA in blood by quantitative polymerase chain reaction. Immunosuppression reduction remains the mainstay of treatment; however, viral clearance is often followed by acute rejection, likely secondary to a delay between immune reconstitution and viral clearance. Impaired cell-mediated immune response to BK virus has been shown to correlate with progression to BK virus nephropathy, while reconstitution of this response correlates with resolution of nephropathy. There is recent research to support monitoring BK virus-specific cell-mediated immune response as a predictor of disease progression and resolution. In this article, we review the current concepts and recent developments in understanding BK virus-associated disease in the context of kidney transplant and outline areas for future research.


Assuntos
Vírus BK/imunologia , Imunossupressores/efeitos adversos , Transplante de Rim/efeitos adversos , Infecções Oportunistas/imunologia , Infecções por Polyomavirus/imunologia , Infecções Tumorais por Vírus/imunologia , Antivirais/uso terapêutico , Vírus BK/efeitos dos fármacos , Vírus BK/patogenicidade , Quimioterapia Combinada , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Interações Hospedeiro-Patógeno , Humanos , Hospedeiro Imunocomprometido , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/tratamento farmacológico , Infecções Oportunistas/virologia , Infecções por Polyomavirus/diagnóstico , Infecções por Polyomavirus/tratamento farmacológico , Infecções por Polyomavirus/virologia , Fatores de Risco , Resultado do Tratamento , Infecções Tumorais por Vírus/diagnóstico , Infecções Tumorais por Vírus/tratamento farmacológico , Infecções Tumorais por Vírus/virologia , Ativação Viral
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