The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600

Massi, Daniela; Brusa, Davide; Merelli, Barbara; Falcone, Chiara; Xue, Gui-Rong; Carobbio, Alessandra; Nassini, Romina; Baroni, Gianna; Tamborini, Elena; Cattaneo, Laura; Audrito, Valentina; Deaglio, Silvia; Mandalà, Mario

doi:10.1093/annonc/mdv255

Cited by 94 publications

(66 citation statements)

References 23 publications

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“…Our previous analysis of this cohort indicated that expression of PD-L1 by tumor cells and TIMC were two independent predictors of response to therapy with BRAFi [27, 31]. We now updated results with a median follow-up of 27.4 months, by which time 45 (64%) patients had progressed and 46 (52.5%) had died.…”

Section: Resultsmentioning

confidence: 86%

PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 86%

PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p

et al. 2017

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“…The binding of the PD-1 molecule to its ligands, programmed death ligand 1 (PD-L1) and 2 (PD-L2), inhibits T-cell signaling, downregulates expression of apoptotic molecules, and regulates the balance between immune tolerance and immunopathology (1). The expression of PD-L1 by tumor cells is one of several means by which cancer cells may evade immune surveillance and has been associated with poor clinical outcomes in patients with cancer (3)(4)(5)(6). The blockade of tumor-mediated PD-L1 signaling restores antitumor immune responses and has emerged as a validated treatment strategy in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

Yan

Wang

Bajaj

et al. 2017

Clinical Cancer Research

109

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Purpose: Nivolumab is a fully human IgG4 monoclonal antiprogrammed death-1 antibody with demonstrated efficacy, including durable responses and prolonged survival, in patients with previously treated, advanced non-small cell lung cancer (NSCLC). Exposure-response (E-R) analyses for efficacy and safety were conducted to inform the benefit-risk assessment of nivolumab in this patient population.Experimental Design: The analyses used clinical trial data from patients with squamous (n ¼ 293) or nonsquamous (n ¼ 354) NSCLC from four clinical trials who received nivolumab doses of 1 to 10 mg/kg every 2 weeks. E-R efficacy analyses were performed by investigating the relationship between timeaveraged nivolumab concentration after the first dose (C avg1 ) and the probability of overall survival by histology. E-R safety analyses examined relationships between nivolumab C avg1 and hazards of adverse events leading to discontinuation or death (AEs-DC/D).Results: Nivolumab exposure was not associated with overall survival [the 95% confidence interval (CI) of effect included 1] in patients with squamous (HR, 0.802; 95% CI, 0.555-1.16) or nonsquamous NSCLC (HR, 0.94; 95% CI, 0.683-1.29). Similarly, nivolumab exposure was not associated with AEs-DC/D in the overall population (HR, 0.917; 95% CI, 0.644-1.31). The risk of AEs-DC/D was similar among patients with squamous or nonsquamous histology.Conclusions: Nivolumab monotherapy demonstrated a wide therapeutic margin, as evidenced by relatively flat E-R relationships over the range of exposures produced by doses of 1 to 10 mg/kg every 2 weeks (Q2W), supporting the use of the initially approved dose of 3 mg/kg Q2W in patients with NSCLC.

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“…Several studies in advanced stage melanoma patients have observed that PD-L1-negative tumors have a worse prognosis than melanoma patients whose tumors express PD-L1 (6-9); however, other studies have reported opposite findings such that the prognostic significance of PD-L1 tumor cell expression remains unresolved (10)(11)(12). What is clear is that PD-L1-negative patients respond less frequently to checkpoint inhibition therapies (5,6).…”

Section: Introductionmentioning

confidence: 99%

PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

Madore

Strbenac

Vilain

et al. 2016

Clinical Cancer Research

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Purpose: Understanding why some melanomas test negative for PD-L1 by IHC may have implications for the application of anti-PD-1 therapies in melanoma management. This study sought to determine somatic mutation and gene expression patterns associated with tumor cell PD-L1 expression, or lack thereof, in stage III metastatic melanoma to better define therapeutically relevant patient subgroups.Experimental Design: IHC for PD-L1 was assessed in 52 American Joint Committee on Cancer stage III melanoma lymph node specimens and compared with specimen-matched comprehensive clinicopathologic, genomic, and transcriptomic data.Results: PD-L1-negative status was associated with lower nonsynonymous mutation (NSM) burden (P ¼ 0.017) and worse melanoma-specific survival [HR ¼ 0.28 (0.12-0.66), P ¼ 0.002] in stage III melanoma. Gene set enrichment analysis identified an immune-related gene expression signature in PD-L1-positive tumors. There was a marked increase in cytotoxic T-cell and macrophage-specific genes in PD-L1-positive melanomas. CD8Ahigh gene expression was associated with better melanomaspecific survival [HR ¼ 0.2 (0.05-0.87), P ¼ 0.017] and restricted to PD-L1-positive stage III specimens. NF1 mutations were restricted to PD-L1-positive tumors (P ¼ 0.041).Conclusions: Tumor negative PD-L1 status in stage III melanoma lymph node metastasis is a marker of worse patient survival and is associated with a poor immune response gene signature. Lower NSM levels were associated with PD-L1-negative status suggesting differences in somatic mutation profiles are a determinant of PD-L1-associated antitumor immunity in stage III melanoma.

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The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV600

Abstract: Our results provide the first proof-of-principle evidence for the predictive and prognostic relevance of PD-L1 immunohistochemical expression and density of immune cell infiltration in BRAF(V600)-mutated MMP treated with BRAFi.

Cited by 94 publications

References 23 publications

PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p

PD-L1 up-regulation in melanoma increases disease aggressiveness and is mediated through miR-17-5p

Nivolumab Exposure–Response Analyses of Efficacy and Safety in Previously Treated Squamous or Nonsquamous Non–Small Cell Lung Cancer

PD-L1 Negative Status is Associated with Lower Mutation Burden, Differential Expression of Immune-Related Genes, and Worse Survival in Stage III Melanoma

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