Innate immune receptor signaling induces transient melanoma dedifferentiation while preserving immunogenicity

Medientyp: E-Artikel

Titel: Innate immune receptor signaling induces transient melanoma dedifferentiation while preserving immunogenicity

Beteiligte: Thier, Beatrice [VerfasserIn]; Zhao, Fang [VerfasserIn]; Stupia, Simone [VerfasserIn]; Brüggemann, Alicia [VerfasserIn]; Koch, Johannes [VerfasserIn]; Schulze, Nina [VerfasserIn]; Horn, Susanne [VerfasserIn]; Coch, Christoph [VerfasserIn]; Hartmann, Gunter [VerfasserIn]; Sucker, Antje [VerfasserIn]; Schadendorf, Dirk [VerfasserIn]; Paschen, Annette [VerfasserIn]

Erschienen: London : BioMed Central, [2023]

Sprache: Englisch

Schlagwörter: Innate immune receptor ; dedifferentiation ; medicine ; immunogenicity ; Medizin

Entstehung:

Anmerkungen: Hinweis: Link zur Erstveröffentlichung URL: http://dx.doi.org/10.1136/jitc-2021-003863

Beschreibung: Background Immune-stimulatory agents, like agonists of the innate immune receptor RIG-I, are currently tested in clinical trials as an intratumoral treatment option for patients with unresectable melanoma, aiming to enhance anti-tumor T cell responses. Switching of melanoma toward a dedifferentiated cell state has recently been linked to T cell and therapy resistance. It remains to be determined whether RIG-I agonists affect melanoma differentiation, potentially leading to T cell resistance. Methods Patient metastases-derived melanoma cell lines were treated with the synthetic RIG-I agonist 3pRNA, and effects on tumor cell survival, phenotype and differentiation were determined. Transcriptomic data sets from cell lines and metastases were analyzed for associations between RIG-I (DDX58) and melanoma differentiation markers and used to define signaling pathways involved in RIG-I- driven dedifferentiation. The impact of 3pRNA-induced melanoma dedifferentiation on CD8 T cell activation was studied in autologous tumor T cell models. Results RIG-I activation by 3pRNA induced apoptosis in a subpopulation of melanoma cells, while the majority of tumor cells switched into a non-proliferative cell state. Those persisters displayed a dedifferentiated cell phenotype, marked by downregulation of the melanocytic lineage transcription factor MITF and its target genes, including melanoma differentiation antigens (MDA). Transition into the MITFlow/MDAlow cell state was JAK-dependent, with some cells acquiring nerve growth factor receptor expression. MITFlow/MDAlow persisters switched back to the proliferative differentiated cell state when RIG-I signaling declined. Consistent with our in vitro findings, an association between melanoma dedifferentiation and high RIG-I (DDX58) levels was detected in transcriptomic data from patient metastases. Notably, despite their dedifferentiated cell phenotype, 3pRNA-induced MITFlow/ MDAlow persisters were still efficiently targeted by autologous CD8 tumor-infiltrating T lymphocytes (TILs). Conclusions Our results demonstrate that RIG-I signaling in melanoma cells drives a transient phenotypic switch toward a non-proliferative dedifferentiated persister cell state. Despite their dedifferentiation, those persisters are highly immunogenic and sensitive toward autologous TILs, challenging the concept of melanoma dedifferentiation as a general indicator of T cell resistance. In sum, our findings support the application of RIG-I agonists as a therapeutic tool for the generation of long-term clinical benefit in non-resectable melanoma.

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