In this study, first author Ervin Ascic, along with co-authors Fritiof Åkerström, Malavika Sreekumar Nair, and others, demonstrated that reprogramming tumor cells in vivo within the immunosuppressive tumor microenvironment (TME) into type 1 conventional dendritic cells (cDC1s) enabled these cells to efficiently present tumor antigens and induce systemic and robust antitumor immunity. This novel strategy showcases a promising new cancer immunotherapy modality. The full article can be found on the Science website following this link.
The Pereira group had previously shown that cancer cells could be reprogrammed in vitro into cDC1-like cells by overexpressing the transcription factors PU.1, IRF8, and BATF3 (collectively referred to as PIB). However, the ex vivo manipulation and re-administration of reprogrammed cells poses significant challenges for clinical application. In this study, in vivo reprogramming was employed directly at the tumor site using a gene therapy approach via adenoviral vectors.
The reprogrammed tumor cells transformed the TME from “cold” to “hot,” recruiting and expanding cytotoxic T cells necessary for effective tumor cell elimination. Another key finding was the formation of tertiary lymphoid structures within the TME. Compared to in vitro methods, in vivo cDC1 reprogramming progressed faster and with higher fidelity. Even in the presence of immunosuppressive cells, reprogrammed cells adopted an immunogenic profile. Furthermore, adenoviral vectors proved to be the most effective system for delivering the cDC1-inducing factors, enabling efficient tumor transduction and reprogramming.
Upon PIB delivery to tumors, the treatment established systemic immunity and mice that survived remained tumor-free upon rechallenge and showed resistance to lung metastasis, all without increased toxic effects on internal organs. These exciting findings lay the groundwork for testing in vivo reprogramming in human clinical trials as the next steps.
Ervin Ascic expressed his enthusiasm and pride in the team's success, extending his gratitude to all co-authors, collaborators, and funding agencies for their support in conducting and financing this study. He said:
Huge congratulations to everyone involved, the members of the Pereira lab, the team of Asgard Therepeutics including Fritiof Åkerström, André Rosa, Xavier Catena, Cristiana Pires and Fabio Rosa but also all the other members of the team, and our collaborators InSphero, the Inge-Marie Svane lab at CCIT-DK in Denmark, as well as Malin Lindstedt, Lennart Greiff, and many others that supported our study. I am really grateful to be conducting my PhD studies in such a unique research environment, which has enabled me to publish my first paper as lead author and will continue to foster my growth as a scientist.