PD-L1 is expressed by a subset of patients with metastatic melanoma (MM) with an unfavorable outcome. Its expression is increased in cells resistant to BRAF or MEK inhibitors (BRAFi or MEKi). However, the function and regulation of expression of PD-L1 remain incompletely understood.After generating BRAFi- and MEKi-resistant cell lines, we observed marked up-regulation of PD-L1 expression. These cells were characterized by a common gene expression profile with up-regulation of genes involved in cell movement. Consistently, in vitro they showed significantly increased invasive properties. This phenotype was controlled in part by PD-L1, as determined after silencing the molecule. Up-regulation of PD-L1 was due to post-transcriptional events controlled by miR-17-5p, which showed an inverse correlation with PD-L1 mRNA. Direct binding between miR-17-5p and the 3’-UTR of PD-L1 mRNA was demonstrated using luciferase reporter assays.In a cohort of 80 BRAF-mutated MM patients treated with BRAFi or MEKi, constitutive expression of PD-L1 in the absence of immune infiltrate, defined the patient subset with the worst prognosis. Furthermore, PD-L1 expression increased in tissue biopsies after the metastatic lesions became resistant to BRAFi or MEKi. Lastly, plasmatic miR-17-5p levels were higher in patients with PD-L1+ than PD-L1- lesions.In conclusion, our findings indicate that PD-L1 expression induces a more aggressive behavior in melanoma cells. We also show that PD-L1 up-regulation in BRAFi or MEKi-resistant cells is partly due to post-transcriptional mechanisms that involve miR-17-5p, suggesting that miR-17-5p may be used as a marker of PD-L1 expression by metastatic lesions and ultimately a predictor of responses to BRAFi or MEKi.
BiR melanoma cells overexpress NAMPT, which acts as a connecting element between BRAF oncogenic signaling and metabolism, becoming an actionable target for this subset of MM patients.
Despite huge efforts towards understanding the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pathogenesis, little is known about the long‐term consequences of the disease. Here, we critically review existing literature about oncogenesis as a potential long‐term effect of SARS‐CoV‐2 infection. Like other viral infections, SARS‐CoV‐2 may promote cancer onset by inhibiting tumor suppressor genes. We conclude that, although unlikely, such hypothesis cannot be excluded a priori and we delineate an experimental approach to address it.
Introduction: The therapy of metastatic melanoma (MM) was radically changed by the introduction of BRAF inhibitors (BRAFi). Even if highly effective in the short term, patients invariably develop resistance in the long term. For this reason other inhibitors as well as alternative or complementary therapeutic strategies are being tested in these patients. Among the immune checkpoint targets of clinical importance is PD-1, which is expressed by T cells and which binds to the PD-L1 ligand, which may be expressed by melanoma cells. We and others showed that PD-L1 is an independent negative prognostic marker for patients with MM. Methods: BRAFi-/MEKi-resistant melanoma cell lines were generated by treating cells with increasing concentrations of BRAFi or MEKi. Resistance, viability and aggressiveness were analyzed by MTT, migration and wound healing assays. Results were confirmed using xenograft models. Resistant cell lines were compared using RNAseq to identify enriched genetic pathways involved in the resistance. Luciferase reporter assay analysis was used to study the direct interactions between the PD-L1 and miR-17-5p. Results: By comparing responses to BRAFi in PD-L1+ and PD-L1- variants of the A375 cell line, we found that PD-L1 expression conferred resistance to BRAFi or MEKi. Conversely, silencing of the molecule restored sensitivity to these drugs. Resistant melanoma cell lines acquired PD-L1 expression and were characterized by a specific genetic profile, with the modulation of genes controlling cell movement and immune responses. Consistently, these cells showed a more aggressive behavior both in vitro and in xenograft models. PD-L1 silencing in resistant cells decreased invasive properties and restored expression of HLA-II molecules. PD-L1 up-regulation was only partly dependent on the paradoxical activation of the MAPK pathway, which characterized resistant cells. In addition, we found that resistance to BRAFi and MEKi down-modulated miR-17-5p, which showed an inverse correlation with PD-L1. Transfection of miR-17-5p into BRAFi-resistant cell lines induced the down-modulation of PD-L1, reduced the aggressive behavior of the cells and partially restored sensitivity to BRAFi. Finally, in the plasma of patients with MM, miR-17-5p was inversely correlated with expression of PD-L1 in the tumor tissue. Conclusions: These data demonstrate a direct link between expression of PD-L1 and resistance to BRAFi, as well as to a more aggressive behavior of melanoma cells. Furthermore, we define a novel post-transcriptional circuit responsible for PD-L1 up-regulation, based on a direct interaction between miR-17-5p and PD-L1 mRNA. Lastly, miR-17-5p plasmatic levels show an inverse correlation with PD-L1 expression by tumor cells, suggesting that they may be useful in monitoring disease outcome and drug sensitivity. Citation Format: Davide Brusa, Aureliano Stingi, Valentina Audrito, Francesca Orso, Sara Serra, Roberta Buonincontri, Francesco Neri, Gianna Baroni, Barbara Merelli, Romina Nassini, Daniela Massi, Salvatore Oliviero, Daniela Taverna, Mario Mandalà, Silvia Deaglio. Up-regulation of PD-L1 in melanoma determines resistance to BRAF and MEK inhibitors, induces a more aggressive phenotype and is partially mediated through post-transcriptional mechanisms involving miR-17-5p. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 241.
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