STING agonist promotes CAR T cell trafficking and persistence in breast cancer

CAR T therapy targeting solid tumors is restrained by limited infiltration and persistence of those cells in the tumor microenvironment (TME). Here, we developed approaches to enhance the activity of CAR T cells using an orthotopic model of locally advanced breast cancer. CAR T cells generated from Th/Tc17 cells given with the STING agonists DMXAA or cGAMP greatly enhanced tumor control, which was associated with enhanced CAR T cell persistence in the TME. Using single-cell RNA sequencing, we demonstrate that DMXAA promoted CAR T cell trafficking and persistence, supported by the generation of a chemokine milieu that promoted CAR T cell recruitment and modulation of the immunosuppressive TME through alterations in the balance of immune-stimulatory and suppressive myeloid cells. However, sustained tumor regression was accomplished only with the addition of anti-PD-1 and anti-GR-1 mAb to Th/Tc17 CAR T cell therapy given with STING agonists. This study provides new approaches to enhance adoptive T cell therapy in solid tumors

Variation of the physicochemical and morphological characteristics of solvent casted poly(vinylidene fluoride) along its binary phase diagram with dimethylformamide

Poly(vinylidene fluoride), PVDF, films and membranes were prepared by solvent casting from dimethylformamide, DMF, by systematically varying polymer/solvent ratio and solvent evaporation temperature. The effect of the processing conditions on the morphology, degree of porosity, mechanical and thermal properties and crystalline phase of the polymer were evaluated. The obtained microstructure is explained by the Flory-Huggins theory. For the binary system, the porous membrane formation is attributed to a spinodal decomposition of the liquid-liquid phase separation. The morphological features were simulated through the correlation between the Gibbs total free energy and the Flory-Huggins theory. This correlation allowed the calculation of the PVDF/DMF phase diagram and the evolution of the microstructure in different regions of the phase diagram. Varying preparation conditions allow tailoring polymer 2 microstructure while maintaining a high degree of crystallinity and a large β crystalline phase content. Further, the membranes show adequate mechanical properties for applications in filtration or battery separator membranes.This work was supported by FEDER through the COMPETE Program and by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Project PEST-C/FIS/UI607/2013, Pest-C/QUI/UI0686/2013 and the project PTDC/CTM-NAN/112574/2009. A.C.L. and C.M.C. thank the support of the FCT (grant SFRH/BD/62507/2009 and SFRH/BD/68499/2010). The authors also thank the support from the COST Action MP1003, 2010 ‘European Scientific Network for Artificial Muscles’ and funding from Matepro–Optimizing Materials and Processes”, ref. NORTE 07-0124-FEDER-000037”, co-funded by the “Programa Operacional Regional do Norte” (ON.2–O Novo Norte), under the “Quadro de Referência Estratégico Nacional”(QREN), through the “Fundo Europeu de Desenvolvimento Regional” (FEDER). The authors also thank the Departamento de Física Química, Universidad del País Vasco, Spain, for hosting part of this research