In vivo dendritic cell reprogramming for cancer immunotherapy

DOI: 10.1126/science.adn9083

This episode delves into a novel approach to cancer immunotherapy: in vivo reprogramming of tumor cells into type 1 conventional dendritic cells (cDC1s) using the transcription factors PU.1, IRF8, and BATF3 (PIB).

Key Findings:

• PIB overexpression reprograms tumor cells into cDC1-like cells in vivo, inducing robust, systemic antitumor immunity in mouse melanoma models.
• Reprogrammed tumor cells remodel the tumor microenvironment (TME), recruiting and expanding polyclonal cytotoxic T cells, and forming tertiary lymphoid structure (TLS)-like formations.
• In vivo reprogramming establishes long-term systemic immunity, protecting mice from tumor re-challenge.
• Reprogramming to immunogenic dendritic-like cells occurs in human tumor spheroids and xenografts, independent of immunosuppression.
• Adenoviral vectors effectively deliver PIB factors to tumors in situ, eliciting potent antitumor responses, even at low doses.
• A gene therapy approach using adenoviral PIB delivery combined with immune checkpoint blockade (ICB) results in complete tumor regression and long-term immunological memory in mice.

Discussion Points:

• The potential of in vivo cDC1 reprogramming as a novel, tumor-agnostic, and personalized immunotherapy modality.
• The role of CD4+ T cells as critical effectors in PIB-mediated antitumor immunity.
• The significance of TLS formation in reprogrammed tumors and its potential as a predictive biomarker.
• The advantages of adenoviral vectors for PIB delivery and their potential for clinical translation.
• The potential synergy of in vivo cDC1 reprogramming with other immunotherapies, such as adoptive T cell therapy or agonistic CD40 antibodies.

Limitations:

• The need to further investigate the contribution of partially versus completely reprogrammed cells to the antitumor response.
• The need to explore the long-term safety and efficacy of this approach in humans.
• The need to optimize delivery methods and reprogramming efficiency for clinical application.

Top Three Takeaways:

• In vivo reprogramming of tumor cells into cDC1s offers a promising new strategy for cancer immunotherapy, effectively turning the tumor itself into a weapon against cancer.
• This approach triggers robust, systemic, and long-lasting antitumor immunity, offering the potential for durable responses and protection from recurrence.
• Adenoviral delivery of PIB provides a clinically translatable platform for a gene therapy approach to cDC1 reprogramming, paving the way for future clinical trials.