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.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:86621 |
| Date | 27 July 2023 |
| Creators | Thier, Beatrice, Zhao, Fang, Stupia, Simone, Brüggemann, Alicia, Koch, Johannes, Schulze, Nina, Horn, Susanne, Coch, Christoph, Hartmann, Gunter, Sucker, Antje, Schadendorf, Dirk, Paschen, Annette |
| Publisher | BioMed Central |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:article, info:eu-repo/semantics/article, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
| Relation | 2051-1426, e003863 |
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