Foxp3-positive macrophages display immunosuppressive properties and promote tumor growth

Identification of a population of Foxp3-expressing suppressive macrophages

La presentación antigénica en el lupus eritematoso sistemático evento determinante del desarrollo de la autoinmunidad y de las direferentes presentaciones clínicas observadas

IP 1115-04-12938Contrato 507-2002Sinopsis divulgativa: En este proyecto se evaluaron algunas células que participan en el desorden inmunológico observado en el Lupus Eritematoso Sistémico (LES), una enfermedad crónica que afecta principalmente mujeres jóvenes y en la que el sistema inmune ataca los propios componentes del organismo, incluyendo el ADN. Entre las células evaluadas se encuentran los monocitos, las células dendríticas y los linfocitos B, denominadas células presentadoras de antigeno (APC

Influence of injection technique, drug formulation and tumor microenvironment on intratumoral immunotherapy delivery and efficacy

Background Intratumoral delivery of immunotherapeutics represents a compelling solution to directly address local barriers to tumor immunity. However, we have previously shown that off-target delivery is a substantial problem during intratumoral injections; this can lead to diminished drug efficacy and systemic toxicities. We have identified three variables that influence intratumoral drug delivery: injection technique, drug formulation and tumor microenvironment. The purpose of this study was to characterize the impact of modifications in each variable on intratumoral drug delivery and immunotherapy efficacy.Methods Intratumoral injections were performed in a hybrid image-guided intervention suite with ultrasound, fluoroscopy and CT scanning capabilities in both rat and mouse syngeneic tumor models. Intratumoral drug distribution was quantified by CT volumetric imaging. The influence of varying needle design and hydrogel-based drug delivery on the immune response to a stimulator of interferon genes (STING) agonist was evaluated using flow cytometry and single cell RNA sequencing. We also evaluated the influence of tumor stiffness on drug injection distribution.Results Variations in needle design, specifically with the use of a multiside hole needle, led to approximately threefold improvements in intratumoral drug deposition relative to conventional end-hole needles. Likewise, delivery of a STING agonist through a multiside hole needle led to significantly increased expression of type I interferon-associated genes and ‘inflammatory’ dendritic cell gene signatures relative to end-hole STING agonist delivery. A multidomain peptide-based hydrogel embedded with a STING agonist led to substantial improvements in intratumoral deposition; however, the hydrogel was noted to generate a strong immune response against itself within the target tumor. Evaluation of tumor stroma on intratumoral drug delivery revealed that there was a greater than twofold improvement in intratumoral distribution in soft tumors (B16 melanoma) compared with firm tumors (MC38 colorectal).Conclusions Injection technique, drug formulation and tumor stiffness play key roles in the accurate delivery of intratumoral immunotherapeutics