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1.
Cell Rep Med ; 5(2): 101397, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-38307029

RESUMO

Microbes are an integral component of the tumor microenvironment. However, determinants of microbial presence remain ill-defined. Here, using spatial-profiling technologies, we show that bacterial and immune cell heterogeneity are spatially coupled. Mouse models of pancreatic cancer recapitulate the immune-microbial spatial coupling seen in humans. Distinct intra-tumoral niches are defined by T cells, with T cell-enriched and T cell-poor regions displaying unique bacterial communities that are associated with immunologically active and quiescent phenotypes, respectively, but are independent of the gut microbiome. Depletion of intra-tumoral bacteria slows tumor growth in T cell-poor tumors and alters the phenotype and presence of myeloid and B cells in T cell-enriched tumors but does not affect T cell infiltration. In contrast, T cell depletion disrupts the immunological state of tumors and reduces intra-tumoral bacteria. Our results establish a coupling between microbes and T cells in cancer wherein spatially defined immune-microbial communities differentially influence tumor biology.


Assuntos
Microbioma Gastrointestinal , Microbiota , Neoplasias Pancreáticas , Camundongos , Animais , Humanos , Linfócitos T/patologia , Neoplasias Pancreáticas/patologia , Comunicação Celular , Microambiente Tumoral
2.
Gastroenterology ; 166(6): 1114-1129, 2024 06.
Artigo em Inglês | MEDLINE | ID: mdl-38244727

RESUMO

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal disease characterized by a spatially heterogeneous tumor microenvironment. Within the PDA microenvironment, cells organize into communities where cell fate is influenced by neighboring cells of diverse ontogeny and function. However, it remains unclear how cell neighborhoods in the tumor microenvironment evolve with treatment and impact clinical outcomes. METHODS: Here, using automated chromogenic multiplex immunohistochemistry and unsupervised computational image analysis of human PDA tumors, we investigated cell neighborhoods in surgically resected tumors from patients with chemotherapy-naïve PDA (n = 59) and neoadjuvant chemotherapy-treated PDA (n = 57). Single cells were defined by lineage markers (CD3, CD8, Foxp3, CD68, CK19), proliferation (Ki67), and neighboring cells. RESULTS: Distinct intratumoral immune and tumor cell subsets were defined by neighboring cells. Higher content of stromal-associated macrophages was seen in chemotherapy-naïve tumors from long-term survivors (overall survival >3 years) compared with short-term survivors (overall survival <1 year), whereas immune-excluded tumor cells were higher in short-term survivors. Chemotherapy-treated vs -naïve tumors showed lower content of tumor-associated T cells and macrophages but similar densities of stromal-associated immune cells. However, proliferating tumor cell subsets with immune-rich neighborhoods were higher in chemotherapy-treated tumors. In a blinded analysis of tumors from patients treated with neoadjuvant chemotherapy, a composite index comprising lower quantities of immune-excluded tumor cells and higher spatially distinct immune cell subsets was associated with prolonged survival. CONCLUSIONS: Together, these data provide new insights into discrete cell communities in PDA and show their clinical relevance.


Assuntos
Carcinoma Ductal Pancreático , Terapia Neoadjuvante , Neoplasias Pancreáticas , Microambiente Tumoral , Humanos , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/terapia , Carcinoma Ductal Pancreático/cirurgia , Microambiente Tumoral/imunologia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/tratamento farmacológico , Masculino , Feminino , Idoso , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Quimioterapia Adjuvante , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo , Resultado do Tratamento , Linfócitos do Interstício Tumoral/imunologia , Proliferação de Células , Imuno-Histoquímica
3.
Sci Immunol ; 8(89): eadj5097, 2023 11 17.
Artigo em Inglês | MEDLINE | ID: mdl-37976347

RESUMO

Myeloid cells facilitate T cell immune evasion in cancer yet are pliable and have antitumor potential. Here, by cotargeting myeloid activation molecules, we leveraged the myeloid compartment as a therapeutic vulnerability in mouse models of pancreatic cancer. Myeloid cells in solid tumors expressed activation receptors including the pattern recognition receptor Dectin-1 and the TNF receptor superfamily member CD40. In mouse models of checkpoint inhibitor-resistant pancreatic cancer, coactivation of Dectin-1, via systemic ß-glucan therapy, and CD40, with agonist antibody treatment, eradicated established tumors and induced immunological memory. Antitumor activity was dependent on cDC1s and T cells but did not require classical T cell-mediated cytotoxicity or blockade of checkpoint molecules. Rather, targeting CD40 drove T cell-mediated IFN-γ signaling, which converged with Dectin-1 activation to program distinct macrophage subsets to facilitate tumor responses. Thus, productive cancer immune surveillance in pancreatic tumors resistant to checkpoint inhibition can be invoked by coactivation of complementary myeloid signaling pathways.


Assuntos
Neoplasias Pancreáticas , Camundongos , Animais , Antígenos CD40 , Imunoterapia
4.
Clin Cancer Res ; 29(17): 3514-3525, 2023 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-37534996

RESUMO

PURPOSE: Determinants of treatment outcomes to chemotherapy-based regimens in metastatic pancreatic ductal adenocarcinoma (PDA) remain ill-defined. Our aim was to examine tissue-based correlates of treatment response and resistance using matched baseline and on-treatment biopsies collected from patients with PDA treated in the first-line metastatic setting. EXPERIMENTAL DESIGN: Patients with treatment-naïve metastatic PDA were enrolled in a Phase II trial (NCT02077881) investigating gemcitabine plus nab-paclitaxel in combination with indoximod, an orally administered small-molecule inhibitor of the IDO pathway. Baseline and on-treatment biopsies (week 8) of metastatic lesions (88% liver) were collected from a cohort of responders (N = 8) and non-responders (N = 8) based on RECIST v1.1 and examined by multiplex IHC and mRNA sequencing. RESULTS: Treatment altered the transcriptional profile of metastatic lesions with a decrease in tumor cell proliferation independent of treatment response. The antiproliferative response was seen in both basal and classical PDA subtypes. PDA subtype was not associated with survival outcomes; instead, genes involved in immune activation distinguished responders from non-responders. Tumor response was associated with an increase in CD3+ and CD8+ T-cell infiltrates into metastatic lesions. A composite of decreased tumor proliferation in response to treatment and increased CD8 T-cell infiltration in metastatic lesions identified responders and associated with a favorable survival outcome. CONCLUSIONS: Our findings suggest that inhibiting cancer cell proliferation alone in PDA is insufficient to produce tumor responses and support a role for tumor-extrinsic mechanisms, such as CD8+ T cells, which combine with the cancer cell proliferation index to define treatment outcomes.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Desoxicitidina , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Paclitaxel , Albuminas , Linfócitos T CD8-Positivos/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/genética
5.
Cancer Immunol Res ; 10(7): 800-810, 2022 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-35507919

RESUMO

Glioblastoma (GBM) is an immunologically "cold" tumor characterized by poor responsiveness to immunotherapy. Standard of care for GBM is surgical resection followed by chemoradiotherapy and maintenance chemotherapy. However, tumor recurrence is the norm, and recurring tumors are found frequently to have acquired molecular changes (e.g., mutations) that may influence their immunobiology. Here, we compared the immune contexture of de novo GBM and recurrent GBM (rGBM) using high-dimensional cytometry and multiplex IHC. Although myeloid and T cells were similarly abundant in de novo and rGBM, their spatial organization within tumors differed and was linked to outcomes. In rGBM, T cells were enriched and activated in perivascular regions and clustered with activated macrophages and fewer regulatory T cells. Moreover, a higher expression of phosphorylated STAT1 by T cells in these regions at recurrence was associated with a favorable prognosis. Together, our data identify differences in the immunobiology of de novo GBM and rGBM and identify perivascular T cells as potential therapeutic targets. See related Spotlight by Bayik et al., p. 787.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Neoplasias Encefálicas/genética , Quimiorradioterapia , Glioblastoma/genética , Humanos , Recidiva Local de Neoplasia/patologia , Prognóstico
6.
Mol Ther ; 28(11): 2367-2378, 2020 11 04.
Artigo em Inglês | MEDLINE | ID: mdl-32730744

RESUMO

B cells infiltrate pancreatic ductal adenocarcinoma (PDAC) and in preclinical cancer models, can suppress T cell immunosurveillance in cancer. Here, we conducted a pilot study to assess the safety and feasibility of administering lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin to target tumor cells along with CART cells redirected against CD19 to deplete B cells. Both CARs contained 4-1BB and CD3ζ signaling domains. Three patients with chemotherapy-refractory PDAC received 1.5 g/m2 cyclophosphamide prior to separate infusions of lentiviral-transduced T cells engineered to express chimeric anti-mesothelin immunoreceptor SS1 (CART-Meso, 3 × 107/m2) and chimeric anti-CD19 immunoreceptor (CART-19, 3 × 107/m2). Treatment was well tolerated without dose-limiting toxicities. Best response was stable disease (1 of 3 patients). CART-19 (compared to CART-Meso) cells showed the greatest expansion in the blood, although persistence was transient. B cells were successfully depleted in all subjects, became undetectable by 7-10 days post-infusion, and remained undetectable for at least 28 days. Together, concomitant delivery of CART-Meso and CART-19 cells in patients with PDAC is safe. CART-19 cells deplete normal B cells but at the dose tested in these 3 subjects did not improve CART-Meso cell persistence.


Assuntos
Antígenos CD19/imunologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Imunoterapia Adotiva , Neoplasias Pancreáticas/terapia , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Depleção Linfocítica/métodos , Mesotelina , Metástase Neoplásica , Estadiamento de Neoplasias , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/patologia , Projetos Piloto , Linfócitos T/metabolismo , Resultado do Tratamento
7.
J Leukoc Biol ; 108(1): 363-376, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32272502

RESUMO

The immune system is a vital determinant of cancer and shapes its trajectory. Notably, the immune reaction to cancer harbors dual potential for suppressing or promoting cancer development and progression. This polarity of the immune response is determined, in part, by the character of the interplay between innate and adaptive immunity. On the one hand, the innate immune compartment is a necessary proponent of cancer immunity by supporting an immunostimulatory state that enables T cell immunosurveillance. However, in the setting of cancer, innate immune cells are commonly polarized with immune-suppressive properties and as a result, orchestrate a tolerogenic niche that interferes with the cytotoxic potential of tumor antigen-specific T cells. Here, we discuss the role of innate immunity as a positive and negative regulator of adaptive immunosurveillance; moreover, we highlight how tumor cells may skew leukocytes toward an immunosuppressive state and, as such, subvert the phenotypic plasticity of the immune compartment to advance disease progression. These observations establish the precedent for novel therapeutic strategies that aim to restore the tumor microenvironment to an immunoreactive state and, in doing so, condition and maintain the immunogenicity of tumors to yield deep and durable responses to immunotherapy.


Assuntos
Imunidade Adaptativa , Imunidade Inata , Vigilância Imunológica , Neoplasias/imunologia , Animais , Humanos , Evasão da Resposta Imune/imunologia , Imunoterapia , Neoplasias/terapia
8.
J Cutan Pathol ; 37(11): 1168-9, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19615031

RESUMO

We present a case of disseminated dermal infection caused by Trichophyton rubrum (T. rubrum). This rare variant of dermatophytosis has an atypical clinical and histopathological presentation and occurs exclusively in immunosuppressed patients. The large, broad, pleomorphic hyphae with scattered budding arthrospores in this variant of T. rubrum infection are unusual and may represent expression of dermatophyte dimorphism previously described in vitro.


Assuntos
Pele/patologia , Tinha/patologia , Trichophyton , Antifúngicos/uso terapêutico , Humanos , Itraconazol/uso terapêutico , Masculino , Pessoa de Meia-Idade , Tinha/tratamento farmacológico , Resultado do Tratamento
9.
Pediatr Neurosurg ; 44(2): 144-7, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18230930

RESUMO

It is essential that various factors be considered when determining the differential diagnosis of congenital scalp lesions, including lesion size, appearance, intracranial extension, underlying medical condition and the embryological germ layer involved. We present the case of a newborn diagnosed as having a sebaceous nevus of Jadassohn scalp lesion. While a common congenital lesion, we describe the unusual presentation at birth as an exophytic nodular lesion. To our knowledge only one other case report of an exophytic congenital lesion has been published.


Assuntos
Nevo Sebáceo de Jadassohn/diagnóstico , Couro Cabeludo/patologia , Dermatopatias/diagnóstico , Diagnóstico Diferencial , Humanos , Recém-Nascido , Masculino , Nevo Sebáceo de Jadassohn/cirurgia , Couro Cabeludo/cirurgia , Dermatopatias/cirurgia
10.
Dermatol Ther ; 20(1): 54-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17403260

RESUMO

Smooth, lustrous nails are a sign of health and beauty in our society and fuel the US$6-billion nail salon industry in the United States. Although many women can use nail cosmetics without adverse consequences, when problems occur it is important to recognize the causes and treat the problem condition. The cornerstone of management of nail cosmetic problems is prevention through education. In spite of efforts to that end, nail salon procedures and materials can cause nail disease that must be recognized and treated in order to restore the nails to health.


Assuntos
Técnicas Cosméticas/efeitos adversos , Doenças da Unha/diagnóstico , Doenças da Unha/terapia , Dermatoses do Pé/diagnóstico , Dermatoses do Pé/etiologia , Dermatoses do Pé/microbiologia , Dermatoses do Pé/patologia , Dermatoses do Pé/terapia , Dermatoses da Mão/diagnóstico , Dermatoses da Mão/etiologia , Dermatoses da Mão/microbiologia , Dermatoses da Mão/patologia , Dermatoses da Mão/terapia , Humanos , Doenças da Unha/etiologia , Doenças da Unha/microbiologia , Doenças da Unha/patologia
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