Allelic and copy-number variations of FcγRs affect granulocyte function and susceptibility for autoimmune blistering diseases.

Low-affinity Fcγ receptors (FcγR) bridge innate and adaptive immune responses. In many autoimmune diseases, these receptors act as key mediators of the pathogenic effects of autoantibodies. Genes encoding FcγR exhibit frequent variations in sequence and gene copy number that influence their functional properties. FcγR variations also affect the susceptibility to systemic autoimmunity, e.g. systemic lupus erythematosus and rheumatoid arthritis. This raises the question whether FcγR variations are also associated with organ-specific autoimmunity, particularly autoantibody-mediated diseases, such as subepidermal autoimmune blistering diseases (AIBD). A multitude of evidence suggests a pathogenic role of neutrophil granulocyte interaction with autoantibodies via FcγR. In a two-stage study, we analyzed whether the FcγR genotype affects neutrophil function and mRNA expression, and consequently, bullous pemphigoid (BP) disease risk. We compared this to findings in pemphigus vulgaris/foliaceus (PV/PF), two Fc-independent AIBDs. Our results indicate that both allele and copy number variation of FcγR genes affect FcγR mRNA expression and reactive oxygen species (ROS) release by granulocytes. Susceptibility of BP was associated with FcγR genotypes that led to a decreased ROS release by neutrophils, indicating an unexpected protective role for these cells. BP and PV/PF differed substantially regarding the FcγR genotype association patterns, pointing towards different disease etiologies.

Immune Cell Infiltration of the Primary Tumor, Not PD-L1 Status, Is Associated With Improved Response to Checkpoint Inhibition in Metastatic Melanoma.

Immune checkpoint inhibition has resulted in dramatic improvements in overall and relapse-free survival in patients with metastatic melanoma. The most commonly used immune checkpoint inhibitors are monoclonal antibodies targeting programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4. Unfortunately, a significant subset of patients fail to respond to these therapies, which has resulted in intense research efforts to identify the factors which are associated with treatment response. To this end, we investigated immune cell infiltration in primary melanomas and melanoma metastases, in addition to tumor cell PD-L1 expression, to determine whether these factors are associated with an improved outcome after immune checkpoint inhibition. Indeed, the extent of the immune cell infiltration in the primary melanoma, measured by the Immunoscore, was associated with a significantly improved response to immune checkpoint inhibition in terms of increased overall survival. However, the Immunoscore did not predict which patients would respond to treatment. The Immunoscore was significantly reduced in metastases when compared to primary melanomas. In contrast, PD-L1 expression, exhaustively tested using four commercially available anti-PD-L1 clones, did not differ significantly between primary tumors and melanoma metastases and was not associated treatment response. Whilst replication in larger, prospective studies is required, our data demonstrates the relevance of immune cell infiltration in the primary melanoma as a novel marker of improved overall survival in response to immune checkpoint inhibition.

Meningeal melanomatosis following discontinuation of dabrafenib: implications for the maintenance of long-term complete remission.

A subset of 10-20% of patients under continuous BRAF inhibitor monotherapy achieve long-term progression-free and overall survival. Definitive criteria for the safe cessation of BRAF inhibitor monotherapy in treatment-responsive melanoma patients are lacking. We report a patient who remained in complete remission (CR) for 5 years under dabrafenib. The treatment was withdrawn because of concerns about cardiac toxicity. Four months thereafter the patient developed neurological symptoms, including diplopia and bilateral visual loss. Meningeal melanomatosis and parenchymal brain metastases were diagnosed. Extracerebral metastases were excluded. Reinduction of dabrafenib, combined with trametinib, led to the rapid relief of the neurological symptoms, and a partial remission was confirmed radiologically. Unfortunately, the response was not maintained and the patient died 9 months later. This observation demonstrates that discontinuation of BRAF inhibition can result in loss of disease control. On the basis of this observation, we suggest that BRAF-targeted therapy should be withdrawn only when the risks of continued treatment exceed the risk for disease relapse. However, future studies are urgently required to confirm and quantify the risk for rapid disease relapse following withdrawal of BRAF inhibitor monotherapy.

Rapid remission of symptomatic brain metastases in melanoma by programmed-death-receptor-1 inhibition.

Although ∼40% of patients with metastatic melanoma develop brain metastases, the presence of brain metastases often precludes enrolment in clinical trials for advanced melanoma. However, the development of symptomatic brain metastases markedly increases mortality. The antiprogrammed-death-receptor-1 antibody pembrolizumab achieves extracranial metastases disease response rates of up to 50%. Here, we report the rapid and sustained response of symptomatic multifocal brain metastases in a melanoma ipilimumab-pretreated patient under pembrolizumab, combined with high-dose dexamethasone therapy during the induction phase of therapy. Complete remission has been maintained for over 1 year of follow-up and has correlated with the response rate observed in the extracranial metastases. Radiological disease response was identified during the first follow-up visit in the absence of adjuvant radiotherapy. This report highlights the need for further clinical studies to specifically address the therapeutic potential of antiprogrammed-death-receptor-1 monotherapy in the management of untreated brain metastases in melanoma.