Epigenetic reprogramming of tumor cell–intrinsic STING function sculpts antigenicity and T cell recognition of melanoma

Menée à l'aide de lignées cellulaires de mélanome humain, cette étude met en évidence un mécanisme par lequel la suppression de la voie de signalisation de la protéine STING dans les cellules tumorales favorise l'échappement immunitaire et la résistance aux immunothérapies à base de lymphocytes T, puis démontre la possibilité de rétablir cette voie de signalisation en inhibant pharmacologiquement la méthylation de l'ADN

Résumé en anglais

Although cancer immunotherapies have shown potential in inducing durable tumor regression in patients with metastatic melanoma, their efficacy remains highly variable and patient specific. Here, we present one strategy to overcome resistance to T cell–based immunotherapies by pharmacologically modulating the STING pathway, a relatively common suppressed DNA-sensing pathway in human melanomas. We show that rescue of this pathway in human melanoma cells using a clinically available DNA methylation inhibitor can augment their antigenicity and recognition by tumor-infiltrating lymphocytes. These findings have important clinical implications for the development of optimal therapeutic protocols that consider the status of tumor-intrinsic STING activity and provide a strategy to design clinical interventions using T cell–based immunotherapies with appropriate patient selection in melanoma.Lack or loss of tumor antigenicity represents one of the key mechanisms of immune escape and resistance to T cell–based immunotherapies. Evidence suggests that activation of stimulator of interferon genes (STING) signaling in tumor cells can augment their antigenicity by triggering a type I IFN-mediated sequence of autocrine and paracrine events. Although suppression of this pathway in melanoma and other tumor types has been consistently reported, the mechanistic basis remains unclear. In this study, we asked whether this suppression is, in part, epigenetically regulated and whether it is indeed a driver of melanoma resistance to T cell–based immunotherapies. Using genome-wide DNA methylation profiling, we show that promoter hypermethylation of cGAS and STING genes mediates their coordinated transcriptional silencing and contributes to the widespread impairment of the STING signaling function in clinically-relevant human melanomas and melanoma cell lines. This suppression is reversible through pharmacologic inhibition of DNA methylation, which can reinstate functional STING signaling in at least half of the examined cell lines. Using a series of T cell recognition assays with HLA-matched human melanoma tumor-infiltrating lymphocytes (TIL), we further show that demethylation-mediated restoration of STING signaling in STING-defective melanoma cell lines can improve their antigenicity through the up-regulation of MHC class I molecules and thereby enhance their recognition and killing by cytotoxic T cells. These findings not only elucidate the contribution of epigenetic processes and specifically DNA methylation in melanoma-intrinsic STING signaling impairment but also highlight their functional significance in mediating tumor-immune evasion and resistance to T cell–based immunotherapies. All study data are included in the article and/or SI Appendix.