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Evolution of a transplantable cancer by adaptation [CTVT_RNAseq_cells]

ABSTRACT: The histocompatibility barrier prevents transmission of both normal and tumour cells between individuals 1, however clonally transmissible cancers in dogs, Tasmania devils and soft-shell clams can naturally transmit as allografts 2. To understand how tumours can escape the histocompatibility barrier, we have serially passaged a mouse melanoma first into syngeneic mice and then into progressively more mismatched mouse strains until a fully allo-transplantable tumour emerged. Here we show that tumour passaging selected for cells with an anti-viral inflammatory signature, characterised by expression of MHC-I, PD-L1, Qa-1 non-classical MHC molecules and the upregulation of intergenic endogenous retroviral elements (ERVs). Knock-out of RNA sensor RIG-I 3 in the transplantable tumour cells resulted in reduced expression of MHC-I, PD-L1 and Qa-1. Antibody-mediated blockade of both PD-L1 and Qa-1 induced tumour regression after transplantation. A similar inflammatory signature was found in human melanomas that respond to anti-PD1 antibody treatment. Thus, an inflammatory anti-viral signature likely induced by RIG-I sensing of ERVs facilitates escape of the mouse melanoma from allogeneic rejection. The results underscore the immunological plasticity of melanoma and reveal an unanticipated role for inflammation in allograft immune evasion.

ORGANISM(S): Mus musculus

PROVIDER: GSE288897 | GEO | 2025/07/29

REPOSITORIES: GEO

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Project description:Background Melanoma cells frequently dedifferentiate in response to inflammation which can increase responses to certain cytokines. Interferon-γ (IFNγ) is an integral part of the anti-tumour immune response and can directly induce both differentiational changes and expression of immunosuppressive proteins in melanoma cells. How the differentiation status of melanoma cells affects IFNγ responses remains unclear. Methods Dedifferentiation of melanoma cells was induced via either siRNA or shRNA mediated MITF knockdown and the cells were subsequently treated with IFNγ. Effects of MITF knockdown and IFNγ treatment on gene expression were evaluated via qPCR and RNA sequencing. A Luminex assay was used to analyse the effects of dedifferentiation and IFNγ treatment on cytokine secretion. Effects on PD-L1 protein expression were analysed via flow cytometry and western blotting. Inhibition of the JAK kinases, NF-κB and STAT3 with small molecule inhibitors, and siRNA mediated knockdown of STAT1 and IRF1 was applied to investigate the molecular mechanism behind IFNγ induced PD-L1 expression in dedifferentiated melanoma cells. The effects of inhibitor treatments and siRNA mediated knockdowns were evaluated via qPCR and western blotting. Bioinformatic analyses of publicly available RNA sequencing data, consisting of 45 patient derived melanoma cell lines, with or without IFNγ treatment, was conducted to assess the generalisability of the in vitro results. Results Dedifferentiation renders 624Mel melanoma cells hypersensitive to IFNγ stimulation in a context-dependent manner, resulting in non-additive upregulation of IFNγ-induced genes, increased PD-L1 protein expression and amplified secretion of CCL2, CXCL10 and IL-10. Furthermore, the intensified PD-L1 protein expression occurs through the JAK-STAT1-IRF1 axis. Lastly, dedifferentiated patient derived melanoma cell lines showed enhanced inflammatory signalling in response to IFNγ compared to differentiated cells, and tended to have higher PD-L1 expression, associated with increased IRF1 expression and activity. Conclusions Together, these findings indicate the existence of a molecular context linking dedifferentiation and IFNγ signalling in melanoma which may lead to immune evasion. Furthermore, these results imply that modulating melanoma differentiation may help shape IFNγ responsiveness.

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Evolution of a transplantable cancer by adaptation [CTVT_RNAseq_cells]

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