In Vivo Dendritic Cell Reprogramming for Cancer Immunotherapy

The Pereira Lab reports for the first time the in vivo reprogramming of cancer cells into type 1 conventional dendritic cells (cDC1s). The study was published in Science and showcases a new cancer immunotherapy modality.

The immunotherapeutic strategies currently employed in cancer treatment (i.e., immune checkpoint blockade) are often ineffective due to cancer immune evasion mechanisms. These mechanisms include the downregulation of antigen presentation pathways, the formation of an immunosuppressive tumor microenvironment (TME), and the exclusion or impairment of professional antigen-presenting cells. Although scarce, cDC1s are fundamental to activate T cell cytotoxic responses and to effectively establish anti-tumor immunity. Until now, cDC1s have not been employed for immunotherapy.

Ascic et al. developed an immunotherapeutic approach based on in vivo cDC1 reprogramming. Intratumoral delivery of transcription factors PU.1, IRF8, and BATF3 (collectively named PIB), previously used to reprogram fibroblasts and tumor cells into cDC1s in vitro, successfully converted tumor cells into cDC1-like cells within the TME and elicited systemic T cell responses that resulted in tumor regressions, abscopal effects and antitumor memory. With this in vivo reprogramming approach, therapy scalability is facilitated, as reprogramming progressed directly at the tumor location using adenoviral vectors for delivery and, therefore, ex vivo cell manufacturing can be circumvented.

The study follows a sequence of using human spheroids, xenografts and syngeneic mouse models with different profiles of immunogenicity, tumor microenvironments, and responsiveness to immunotherapies. When compared to in vitro, in vivo cDC1 reprogramming of tumor cells showed increased speed and efficiency. Reprogrammed cells remodeled the TME from “cold” to “hot” and promoted the recruitment and expansion of cytotoxic T cells that led to tumor regression and stimulated systemic, long-lasting anti-tumor immunity. The development of tertiary lymphoid-like structures in the TME was also a significant finding, as these structures serve as centers of immunological activity and correlate with immune checkpoint efficacy in humans. Additionally, reprogramming to cDC1s worked in synergy with immune checkpoint blockade. The immunosuppressive environment did not hamper the acquisition of an immunogenic cDC1-like phenotype and antigen presentation function. Testing this strategy as a potential gene therapy for cancer, Ascic et al. performed delivery and dose-dependency assays, and reported that adenoviral vectors could mediate efficient cDC1 reprogramming in situ. In conclusion, in vivo cDC1 reprogramming is a robust, off-the-shelf strategy to bypass cancer immunotherapy resistance hurdles and fully harness the functional features of cDC1s. Hence, in vivo cDC1 reprogramming walked the first lane to be later evaluated in patients, excitingly changing the current picture of “untreatable” tumors in the field of immunotherapy.

This study was directed by the amazing PhD student Ervin Aščić and the Pereira lab members Malavika Sreekumar Nair, Ilia Kurochkin, Olga Zimmermannova, Tommaso Ballocci and Maria de Rosa Torres in close collaboration with Asgard Therapeutics. We are grateful for the funding agencies for making this project possible: European Research Council (ERC), Marie Skłodowska-Curie program, Cancerfonden, Swedish Research Council, NovoNordisk Fonden, Eurostars-2 Joint Program, Swedish Innovation Agency, ALF, and FCT.

Read it here