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1.
Proc Natl Acad Sci U S A ; 119(17): e2107394119, 2022 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-35439048

RESUMEN

Tumor associated macrophages (TAMs), which differentiate from circulating monocytes, are pervasive across human cancers and comprise heterogeneous populations. The contribution of tumor-derived signals to TAM heterogeneity is not well understood. In particular, tumors release both soluble factors and extracellular vesicles (EVs), whose respective impact on TAM precursors may be different. Here, we show that triple negative breast cancer cells (TNBCs) release EVs and soluble molecules promoting monocyte differentiation toward distinct macrophage fates. EVs specifically promoted proinflammatory macrophages bearing an interferon response signature. The combination in TNBC EVs of surface CSF-1 promoting survival and cargoes promoting cGAS/STING or other activation pathways led to differentiation of this particular macrophage subset. Notably, macrophages expressing the EV-induced signature were found among patients' TAMs. Furthermore, higher expression of this signature was associated with T cell infiltration and extended patient survival. Together, this data indicates that TNBC-released CSF-1-bearing EVs promote a tumor immune microenvironment associated with a better prognosis in TNBC patients.


Asunto(s)
Vesículas Extracelulares , Neoplasias de la Mama Triple Negativas , Vesículas Extracelulares/fisiología , Humanos , Macrófagos , Neoplasias de la Mama Triple Negativas/patología
2.
Science ; 360(6394)2018 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-29773669

RESUMEN

The majority of patients with pancreatic ductal adenocarcinoma (PDA) develop metastatic disease after resection of their primary tumor. We found that livers from patients and mice with PDA harbor single disseminated cancer cells (DCCs) lacking expression of cytokeratin 19 (CK19) and major histocompatibility complex class I (MHCI). We created a mouse model to determine how these DCCs develop. Intraportal injection of immunogenic PDA cells into preimmunized mice seeded livers only with single, nonreplicating DCCs that were CK19- and MHCI- The DCCs exhibited an endoplasmic reticulum (ER) stress response but paradoxically lacked both inositol-requiring enzyme 1α activation and expression of the spliced form of transcription factor XBP1 (XBP1s). Inducible expression of XBP1s in DCCs, in combination with T cell depletion, stimulated the outgrowth of macrometastatic lesions that expressed CK19 and MHCI. Thus, unresolved ER stress enables DCCs to escape immunity and establish latent metastases.


Asunto(s)
Carcinoma Ductal Pancreático/secundario , Estrés del Retículo Endoplásmico/inmunología , Neoplasias Hepáticas/secundario , Neoplasias Pancreáticas/patología , Escape del Tumor , Animales , Carcinoma Ductal Pancreático/inmunología , Endorribonucleasas/genética , Endorribonucleasas/metabolismo , Genes MHC Clase I , Ingeniería Genética , Humanos , Queratina-19/metabolismo , Neoplasias Hepáticas/inmunología , Depleción Linfocítica , Ratones , Ratones Endogámicos C57BL , Neoplasias Experimentales/genética , Neoplasias Experimentales/inmunología , Neoplasias Experimentales/secundario , Neoplasias Pancreáticas/inmunología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Linfocitos T/inmunología , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/metabolismo
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