1281 A cancer immunotherapy modality based on dendritic cell reprogramming in vivo
Year: 2024
Type: conference-abstract
Abstract: Background Immunotherapy modalities have revolutionized cancer treatment and depend on the establishment of T cell responses for long-term survival. However, generalized success has been hampered by insufficient antigen presentation, an immunosuppressive tumor microenvironment and exclusion of immunogenic cells. Conventional dendritic cells type 1 (cDC1s) are a rare subset of dendritic cells that are vital in the recruitment and activation of cytotoxic T cell responses for effective immunity across many cancer types. Despite the unique role of cDC1 in antitumor immunity, their functional properties have not been deployed yet for immunotherapy. Methods Here, we developed a gene therapy approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8 and BATF3, which enable them to present antigens as cDC1. We assessed immune responses elicited by cDC1 reprogramming in vivo as monotherapy or in combination with immune checkpoint inhibitors, characterized changes in tumor-infiltrating and peripheral immune cells by microscopy, flow cytometry and scRNA-seq and evaluated reprogramming in human xenografts and cancer spheroids in the presence of immunosuppressive components. Results cDC1 reprogramming in vivo progressed fast and more efficient when compared to in vitro and resulted in cDC1-like tumor cells with increased fidelity in the tumor microenvironment. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced complete tumor regressions, and established systemic immunity in different mouse melanoma models. Remodeling of the tumor environment was accompanied by the induced formation of tertiary lymphoid structures and CD4+ T cells were critical as antibody-mediated depletion abolished anti-tumor responses. Survivor mice remained tumor-free upon subcutaneous re-challenge and were resistant to metastatic lung colonization. We show that in situ cDC1 reprogramming synergized with immune checkpoint blockade, was independent of the endogenous cDC1 compartment and led to the establishment of long-term immunological memory, while no increased autoreactive responses could be observed. In human tumor spheroids and xenografts, reprogramming resulted in cDC1-like cells that had a mature and immunogenic signature and resemble more closely natural cDC1. Importantly, reprogramming in human cancers progressed independently of an immunosuppressive environment, which usually limits immunotherapy efficacy. Conclusions We provide proof-of-principle that cDC1 reprogramming in situ represents an off-the-shelf, yet personalized immunotherapy modality that is able to orchestrate systemic, durable, and safe antitumor immunity. This study paves the way for first-in-human trials and lays the foundation for a new class of immunotherapy modalities based on the unique function of immune cell subsets generated in vivo through cellular reprogramming. Ethics Approval Animal care and experimental procedures were performed in accordance with the Swedish federal regulations after approval of the ethical permit (Dnr. 5.8.18-13739/2023) from the Swedish Board of Agriculture.
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
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,490
OpenAlex ID: W4404064157