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Cell ; 184(8): 2033-2052.e21, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33765443

RESUMO

Metastasis is the leading cause of cancer-related deaths, and greater knowledge of the metastatic microenvironment is necessary to effectively target this process. Microenvironmental changes occur at distant sites prior to clinically detectable metastatic disease; however, the key niche regulatory signals during metastatic progression remain poorly characterized. Here, we identify a core immune suppression gene signature in pre-metastatic niche formation that is expressed predominantly by myeloid cells. We target this immune suppression program by utilizing genetically engineered myeloid cells (GEMys) to deliver IL-12 to modulate the metastatic microenvironment. Our data demonstrate that IL12-GEMy treatment reverses immune suppression in the pre-metastatic niche by activating antigen presentation and T cell activation, resulting in reduced metastatic and primary tumor burden and improved survival of tumor-bearing mice. We demonstrate that IL12-GEMys can functionally modulate the core program of immune suppression in the pre-metastatic niche to successfully rebalance the dysregulated metastatic microenvironment in cancer.


Assuntos
Terapia de Imunossupressão , Células Mieloides/metabolismo , Imunidade Adaptativa , Animais , Linhagem Celular Tumoral , Engenharia Genética , Humanos , Interleucina-12/genética , Interleucina-12/metabolismo , Pulmão/metabolismo , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células Mieloides/citologia , Células Mieloides/imunologia , Metástase Neoplásica , Rabdomiossarcoma/metabolismo , Rabdomiossarcoma/patologia , Taxa de Sobrevida , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral
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