RESUMEN

The tumor microenvironment (TME) in pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance, which enables disease to progress unabated by adaptive immunity. However, the drivers of this tolerogenic program are incompletely defined. In this study, we found that NLRP3 promotes expansion of immune-suppressive macrophages in PDA. NLRP3 signaling in macrophages drives the differentiation of CD4+ T cells into tumor-promoting T helper type 2 cell (Th2 cell), Th17 cell, and regulatory T cell populations while suppressing Th1 cell polarization and cytotoxic CD8+ T cell activation. The suppressive effects of NLRP3 signaling were IL-10 dependent. Pharmacological inhibition or deletion of NLRP3, ASC (apoptosis-associated speck-like protein containing a CARD complex), or caspase-1 protected against PDA and was associated with immunogenic reprogramming of innate and adaptive immunity within the TME. Similarly, transfer of PDA-entrained macrophages or T cells from NLRP3-/- hosts was protective. These data suggest that targeting NLRP3 holds the promise for the immunotherapy of PDA.

Asunto(s)

Inmunidad Adaptativa , Macrófagos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Transducción de Señal , Animales , Proteínas Reguladoras de la Apoptosis/deficiencia , Proteínas Reguladoras de la Apoptosis/metabolismo , Proteínas Adaptadoras de Señalización CARD , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Caspasa 1/deficiencia , Caspasa 1/metabolismo , Diferenciación Celular , Proliferación Celular , Reprogramación Celular , Eliminación de Gen , Humanos , Terapia de Inmunosupresión , Ratones Endogámicos C57BL , Proteína Adaptadora de Señalización NOD2/metabolismo , Células Estrelladas Pancreáticas/metabolismo , Células Estrelladas Pancreáticas/patología , Linfocitos T/inmunología , Microambiente Tumoral , Neoplasias Pancreáticas