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1.
Sci Transl Med ; 15(711): eadd9990, 2023 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-37647386

RESUMO

Myeloid cells in the tumor microenvironment (TME) can exist in immunosuppressive and immunostimulatory states that impede or promote antitumor immunity, respectively. Blocking suppressive myeloid cells or increasing stimulatory cells to enhance antitumor immune responses is an area of interest for therapeutic intervention. Triggering receptor expressed on myeloid cells-1 (TREM1) is a proinflammatory receptor that amplifies immune responses. TREM1 is expressed on neutrophils, subsets of monocytes and tissue macrophages, and suppressive myeloid populations in the TME, including tumor-associated neutrophils, monocytes, and tumor-associated macrophages. Depletion or inhibition of immunosuppressive myeloid cells, or stimulation by TREM1-mediated inflammatory signaling, could be used to promote an immunostimulatory TME. We developed PY159, an afucosylated humanized anti-TREM1 monoclonal antibody with enhanced FcγR binding. PY159 is a TREM1 agonist that induces signaling, leading to up-regulation of costimulatory molecules on monocytes and macrophages, production of proinflammatory cytokines and chemokines, and enhancement of T cell activation in vitro. An antibody against mouse TREM1, PY159m, promoted antitumor efficacy in syngeneic mouse tumor models. These results suggest that PY159-mediated agonism of TREM1 on tumoral myeloid cells can promote a proinflammatory TME and offer a promising strategy for immunotherapy.


Assuntos
Monócitos , Células Mieloides , Animais , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Modelos Animais de Doenças , Imunossupressores , Macrófagos , Receptor Gatilho 1 Expresso em Células Mieloides
2.
Cell Rep ; 37(3): 109844, 2021 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-34686340

RESUMO

Converting checkpoint inhibitor (CPI)-resistant individuals to being responsive requires identifying suppressive mechanisms. We identify TREM2+ tumor-associated macrophages (TAMs) as being correlated with exhausted CD8+ tumor-infiltrating lymphocytes (TILs) in mouse syngeneic tumor models and human solid tumors of multiple histological types. Fc domain-enhanced anti-TREM2 monoclonal antibody (mAb) therapy promotes anti-tumor immunity by elimination and modulation of TAM populations, which leads to enhanced CD8+ TIL infiltration and effector function. TREM2+ TAMs are most enriched in individuals with ovarian cancer, where TREM2 expression corresponds to disease grade accompanied by worse recurrence-free survival. In an aggressive orthotopic ovarian cancer model, anti-TREM2 mAb therapy drives potent anti-tumor immunity. These results highlight TREM2 as a highly attractive target for immunotherapy modulation in individuals who are refractory to CPI therapy and likely have a TAM-rich tumor microenvironment.


Assuntos
Antineoplásicos Imunológicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Inibidores de Checkpoint Imunológico/farmacologia , Glicoproteínas de Membrana/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Receptores Imunológicos/antagonistas & inibidores , Macrófagos Associados a Tumor/efeitos dos fármacos , Animais , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Técnicas de Cocultura , Resistencia a Medicamentos Antineoplásicos , Feminino , Células HEK293 , Humanos , Ativação Linfocitária/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Receptores Imunológicos/metabolismo , Transdução de Sinais , Células Tumorais Cultivadas , Microambiente Tumoral , Macrófagos Associados a Tumor/imunologia , Macrófagos Associados a Tumor/metabolismo
3.
J Clin Invest ; 122(9): 3159-69, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22922254

RESUMO

Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects.


Assuntos
Precursor de Proteína beta-Amiloide/líquido cefalorraquidiano , Transporte Axonal , Cromogranina B/líquido cefalorraquidiano , Neuregulina-1/líquido cefalorraquidiano , Doença de Parkinson Secundária/líquido cefalorraquidiano , alfa-Sinucleína/líquido cefalorraquidiano , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Cromogranina B/metabolismo , Feminino , Humanos , Cinética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/metabolismo , Mutação de Sentido Incorreto , Neuregulina-1/metabolismo , Nocodazol/farmacologia , Noscapina/farmacologia , Paclitaxel/farmacologia , Doença de Parkinson Secundária/induzido quimicamente , Superóxido Dismutase/genética , Superóxido Dismutase-1 , Moduladores de Tubulina/farmacologia , alfa-Sinucleína/metabolismo , Proteínas tau/metabolismo
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