Askmyr, D. | bioRxiv Science

bioRxiv2024

A cancer immunotherapy modality based on dendritic cell reprogramming in vivo

Immunotherapy leads to long-term survival of cancer patients, yet generalized success has been hampered by insufficient antigen presentation and exclusion of immunogenic cells from the tumor microenvironment. Here, we developed an approach to reprogram tumor cells in vivo by adenoviral delivery of the transcription factors PU.1, IRF8, and BATF3, which enabled them to present antigens as type 1 conventional dendritic cells. Reprogrammed tumor cells remodeled their tumor microenvironment, recruited, and expanded polyclonal cytotoxic T cells, induced complete tumor regressions, and established long-term systemic immunity in different mouse melanoma models. In human tumor spheroids and xenografts, reprogramming to immunogenic dendritic-like cells progressed independently of immunosuppression, which usually limits immunotherapy. Our study paves the way for first-in-human trials and other applications of immune cell reprogramming in vivo. One-Sentence SummaryReprogramming of tumor cells to cDC1-like cells in vivo elicits systemic and long-term antitumor immunity.

immunology↗

bioRxiv2022

Single-cell analysis of myeloid cells in HPV+ tonsillar cancer

The incidence of Human Papillomavirus positive (HPV+) tonsillar cancer has been sharply rising during the last two decades. Myeloid cells represent an appropriate therapeutic target due to their ability to orchestrate antigen-specific immunity within the tonsil, the availability of viral antigens, and the proximity of the tumor and the underlying lymphoid tissue. However, the interrelationship of steady-state and inflammatory myeloid cell subsets, and their impact on patient survival remains unexplored. Here, we used single-cell RNA-sequencing to map the myeloid compartment in HPV+ tonsillar cancer. Our analysis unveiled the existence of four dendritic cell lineages, two macrophage polarization processes, and their sequential maturation profiles. We observed an expansion of the myeloid compartment in HPV+ tonsillar cancer, accompanied by interferon-induced cellular responses both in DCs and monocyte-macrophages. Within the DC lineages, we describe a balance shift in the frequency of progenitor and mature cDC favoring the cDC1 lineage in detriment of cDC2s, in HPV+ lesions. Furthermore, we observed that all DC lineages apart from DC5s matured into a common activated DC profile. In turn, the monocyte-macrophage lineage was subjected to early monocyte polarization events, which gave raise to inflammatory-activated, and chemokine-producing macrophages. We validated the existence of most of the single-cell RNA-seq clusters using 26-plex flow cytometry, and described a positive impact of cDC1, activated DCs and macrophages in patient survival using signature scoring. The current study contributes towards the understanding of myeloid ontogeny and dynamics in human papilloma driven tonsillar cancer, and details myeloid biomarkers that can be used to predict therapy effects and assess patient prognosis.

immunology↗