Publications
In Vivo Dendritic Cell Reprogramming for Cancer Immunotherapy
September 5, 2024
Science
Ervin Ascic, Fritiof Åkerström, Malavika Sreekumar Nair, André Rosa, Ilia Kurochkin, Olga Zimmermannova, Xavier Catena, Nadezhda Rotankova, Charlotte Veser, Michal Rudnik, Tommaso Ballocci, Tiffany Schärer, Xiaoli Huang, Maria de Rosa Torres, Emilie Renaud, Marta Velasco Santiago, Özcan Met, David Askmyr, Malin Lindstedt, Lennart Greiff, Laure-Anne Ligeon, Irina Agarkova, Inge Marie Svane, Cristiana F. Pires, Fábio F. Rosa, and Carlos-Filipe Pereira
Related Data:
Mouse T Cell Single-Cell RNA- and TCR-Sequencing Human Spheroid Single-Cell RNA-SequencingResources:
Abstract
Immunotherapy can lead to long-term survival for some cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced tumor regressions, and established long-term systemic immunity in multiple mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for human clinical trials of in vivo immune cell reprogramming for cancer immunotherapy.
Image credit: Joana Carvalho
Graphical Abstract
In vivo reprogramming of tumor cells to dendritic cells. (1) Adenoviral delivery of PIB to tumors generates cDC1-like cells, marked by XCR1, CLEC9A, MHC-I/II and CD40 expression. (2) Reprogrammed tumor cells promote the formation of tertiary lymphoid structures, infiltration of CD8+ T cells and polyclonal cytotoxic CD4+ T cells, (3) leading to tumor regression, immunological memory and the control of abscopal tumors and lung metastasis.
Web-Based Application for Data
https://cellreprolab.shinyapps.io/inVivo_DC1_atlas
Reprogramming Is Key to Unlock Antitumor Immunity – About the Cover
This cover depicts a cancer immunotherapy modality by reprogramming tumor cells within the tumor microenvironment into dendritic cells that glow as a light bulb in the dark symbolizing the dawn of a new class of cancer treatments. The key, an adenoviral vector, delivers the reprogramming factors PU.1, IRF8 and BATF3 to the tumor cells in vivo and unlocks an immunogenic program in the tumor cells to present antigens as type 1 dendritic cells. Reprogrammed cells ultimately illuminate the way for the immune system in cold and “dark” tumors to generate robust, long-lasting, and systemic antitumor responses.
Image credit: Joana Carvalho