Filipe Pereira: In vivo dendritic cell reprogramming for cancer immunotherapy

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In this study, we demonstrated that reprogramming tumor cells in vivo within the immunosuppressive tumor microenvironment (TME) into type 1 conventional dendritic cells (cDC1s) enabled them to efficiently present tumor antigens and elicit systemic and safe antitumor immunity, showcasing a new immunotherapy modality for cancer.

We have previously demonstrated that cancer cells can be reprogrammed in vitro to cDC1-like cells by overexpressing the specific combination of transcription factors PU.1, IRF8 and BATF3 (collectively named PIB). However, ex vivo cell manipulation and re-administration of these reprogrammed cells poses a significant challenge for clinical translation. Here, we employed in vivo reprogramming directly at the tumor location and developed a gene therapy approach using adenoviral vectors.

Reprogrammed tumor cells reshaped the TME from ‘cold’ to ‘hot’ and recruited and expanded T cells that are required for the killing of tumor cells. The development of tertiary lymphoid structures within the TME was also a significant finding. When compared to in vitro, in vivo cDC1 reprogramming of tumor cells progressed faster and with better fidelity. Reprogrammed cells acquired an immunogenic profile, even in the presence of immunosuppressive cells.

We lastly compared delivery systems for the cDC1-inducing factors and found that adenoviral vectors combine efficient tumor transduction with reprogramming towards cDC1-like cells. Using adenoviral vectors, we then delivered PIB to tumors and observed the establishment of systemic immunity. Survivor mice remained tumor-free upon rechallenge and showed resistance to lung metastasis without developing toxicities to internal organs. The results of this study excitingly set the stage to test in vivo reprogramming in human trials!

This study was directed by the amazing PhD student Ervin Ascic with fantastic contributions from the Pereira Lab team members: Malavika Sreekumar Nair, Ilia Kurochkin, Olga Zimmermann, Tommaso Ballocci, and Maria de Rosa Torres at the Lund Stem Cell Center, WCMM LU , Lund University. The study was executed in close collaboration Asgard Therapeutics with critical contributions from Cristiana Pires, Fabio Rosa, Fritiof Åkerström, André Rosa and Xavier Catena. We are very grateful to our collaborators InSphero , CCITdk, Malin Lindstedt, Lennart Greiff, Inge Marie Svane, Özcan Met, Irina Agarkova and many others that supported the execution of this project.

We also thank the funding agencies European Research Council (ERC), Marie Skłodowska-Curie program, Cancerfonden, Vetenskapsrådet / Swedish Research Council, NovoNordisk Fonden, Eurostars-2 Joint Program, Vinnova, ALF, and Fundação para a Ciência e a Tecnologia (FCT) for making this study possible!”

In vivo dendritic cell reprogramming for cancer immunotherapy

Authors: 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, Carlos-Filipe Pereira