The immunostimulatory RNA RN7SL1 enables CAR-T cells to enhance autonomous and endogenous immune function.

Autor:	Johnson LR; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Lee DY; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Eacret JS; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Ye D; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., June CH; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: cjune@upenn.edu., Minn AJ; Department of Radiation Oncology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Mark Foundation Center for Immunotherapy, Immune Signaling, and Radiation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: andyminn@upenn.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2021 Sep 16; Vol. 184 (19), pp. 4981-4995.e14. Date of Electronic Publication: 2021 Aug 30.
DOI:	10.1016/j.cell.2021.08.004
Abstrakt:	Poor tumor infiltration, development of exhaustion, and antigen insufficiency are common mechanisms that limit chimeric antigen receptor (CAR)-T cell efficacy. Delivery of pattern recognition receptor agonists is one strategy to improve immune function; however, targeting these agonists to immune cells is challenging, and off-target signaling in cancer cells can be detrimental. Here, we engineer CAR-T cells to deliver RN7SL1, an endogenous RNA that activates RIG-I/MDA5 signaling. RN7SL1 promotes expansion and effector-memory differentiation of CAR-T cells. Moreover, RN7SL1 is deployed in extracellular vesicles and selectively transferred to immune cells. Unlike other RNA agonists, transferred RN7SL1 restricts myeloid-derived suppressor cell (MDSC) development, decreases TGFB in myeloid cells, and fosters dendritic cell (DC) subsets with costimulatory features. Consequently, endogenous effector-memory and tumor-specific T cells also expand, allowing rejection of solid tumors with CAR antigen loss. Supported by improved endogenous immunity, CAR-T cells can now co-deploy peptide antigens with RN7SL1 to enhance efficacy, even when heterogenous CAR antigen tumors lack adequate neoantigens. Competing Interests: Declaration of interests A.J.M. has received research funding from Merck. He is a scientific advisor for Takeda, H3Biomedicine, Related Sciences, and Xilio. A.J.M. is an inventor on patents related to the IFN pathway. A.J.M., L.R.J., and C.H.J. are inventors on a filed patent related to modified CAR-T cells. C.H.J. reports research funding from Novartis, and he is a scientific founder of Tmunity Therapeutics. A.J.M., C.H.J., and L.R.J. are scientific founders for Project 5 Therapeutics. C.H.J. also works under a research collaboration involving the University of Pennsylvania and the Novartis Institute of Biomedical Research and is an inventor of intellectual property licensed by the University of Pennsylvania to Novartis. C.H.J. is on the board of directors for AC Immune and is a scientific advisor for BluesphereBio, Cabaletta, Carisma, Cartography, Cellares, Celldex, DeCART, Decheng, Poseida, Verismo, WIRB Copernicus, and Ziopharm. (Copyright © 2021. Published by Elsevier Inc.)
Databáze:	MEDLINE
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