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1.
Cancer Discov ; 14(7): 1252-1275, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38427556

RESUMEN

Bone is the most common site of breast cancer metastasis. Bone metastasis is incurable and is associated with severe morbidity. Utilizing an immunocompetent mouse model of spontaneous breast cancer bone metastasis, we profiled the immune transcriptome of bone metastatic lesions and peripheral bone marrow at distinct metastatic stages, revealing dynamic changes during the metastatic process. We show that cross-talk between granulocytes and T cells is central to shaping an immunosuppressive microenvironment. Specifically, we identified the PD-1 and TIGIT signaling axes and the proinflammatory cytokine IL1ß as central players in the interactions between granulocytes and T cells. Targeting these pathways in vivo resulted in attenuated bone metastasis and improved survival, by reactivating antitumor immunity. Analysis of patient samples revealed that TIGIT and IL1ß are prominent in human bone metastasis. Our findings suggest that cotargeting immunosuppressive granulocytes and dysfunctional T cells may be a promising novel therapeutic strategy to inhibit bone metastasis. Significance: Temporal transcriptome profiling of the immune microenvironment in breast cancer bone metastasis revealed key communication pathways between dysfunctional T cells and myeloid derived suppressor cells. Cotargeting of TIGIT and IL1ß inhibited bone metastasis and improved survival. Validation in patient data implicated these targets as a novel promising approach to treat human bone metastasis.


Asunto(s)
Neoplasias Óseas , Neoplasias de la Mama , Células Supresoras de Origen Mieloide , Receptores Inmunológicos , Animales , Ratones , Femenino , Neoplasias Óseas/secundario , Neoplasias Óseas/inmunología , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Humanos , Receptores Inmunológicos/antagonistas & inhibidores , Receptores Inmunológicos/metabolismo , Microambiente Tumoral/inmunología
2.
Cell Rep ; 37(7): 110026, 2021 11 16.
Artículo en Inglés | MEDLINE | ID: mdl-34788631

RESUMEN

Liver-resident macrophages Kupffer cells (KCs) and infiltrating Ly6Chi monocytes both contribute to liver tissue regeneration in various pathologies but also to disease progression upon disruption of orderly consecutive regeneration cascades. Little is known about molecular pathways that regulate their differentiation, maintenance, or inflammatory behavior during injury. Here, we show that copper metabolism MURR1 domain (COMMD)10-deficient KCs adopt liver-specific identity. Strikingly, COMMD10 deficiency in KCs and in other tissue-resident macrophages impedes their homeostatic survival, leading to their continuous replacement by Ly6Chi monocytes. While COMMD10 deficiency in KCs mildly worsens acetaminophen-induced liver injury (AILI), its deficiency in Ly6Chi monocytes results in exacerbated and sustained hepatic damage. Monocytes display unleashed inflammasome activation and a reduced type I interferon response and acquire "neutrophil-like" and lipid-associated macrophage differentiation fates. Collectively, COMMD10 appears indispensable for KC and other tissue-resident macrophage survival and is an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.


Asunto(s)
Péptidos y Proteínas de Señalización Intracelular/metabolismo , Macrófagos del Hígado/metabolismo , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Diferenciación Celular/genética , Supervivencia Celular , Hematopoyesis , Inflamasomas/metabolismo , Inflamación/patología , Péptidos y Proteínas de Señalización Intracelular/genética , Macrófagos del Hígado/fisiología , Hígado/citología , Hígado/lesiones , Masculino , Ratones , Ratones Endogámicos C57BL , Monocitos/metabolismo
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