Metastatic melanoma is associated with poor outcomes and is largely refractory to the historic standard of care. In recent years, the development of targeted small-molecule inhibitors and immunotherapy has revolutionised the care and improved the overall survival of these patients. Therapies targeting BRAF and MEK to block the mitogen-activated protein kinase (MAPK) pathway were the first to show unprecedented clinical responses. Following these encouraging results, antibodies targeting immune checkpoint inhibition molecules cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell death (PD)-1, and PD-ligand 1 (PD-L1) demonstrated sustained tumour regression in a significant subset of patients by enabling an anti-tumour immunologic response. Despite these landmark changes in practice, the majority of patients are either intrinsically resistant or rapidly acquire resistance to MAPK pathway inhibitors and immune checkpoint blockade treatment.
Immunotherapy is currently changing the landscape of oncology.
Nowadays the standard of care in metastatic or unresectable melanoma patients includes immunomodulating modalities such as anti-PD-1 drugs (nivolumab, pembrolizumab) and the anti-CTLA-4 antibody ipilimumab.
The improvements of progression free survival and overall survival connected with those treatments were unprecedented and have been confirmed in stage 3 trials.
Nivolumab is associated with significant improvements in overall survival and progression-free survival, as compared with dacarbazine, among previously untreated patients who had metastatic melanoma without a BRAF mutation. 
PD-1/P-L1 blockade has promising effects in melanoma immunotherapy.
Removing the so-called " brakes” on T cell immune responses by blocking the PD-1/PD-L1 check point should boost anti-tumour immunity and provide durable tumour regression for cancer patients.
However, 30–60% of patients show no response to PD-1/PD-L1 blockade. 
It is believed that mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumour site, immunosuppressive factors in the tumour microenvironment and a range of tumour-intrinsic factors.
Tumour regression after therapeutic PD-1 blockade requires pre-existing CD8(+) T cells that are negatively regulated by PD-1/PD-L1-mediated adaptive immune resistance. 
Treatment with an anti-PD-1 mAb also increases the frequency of IFN-gamma and TNF producing CD4+ T-cells specific for melanoma-associated antigens. 
Biomarkers to predict outcome after immune-checkpoint blockade are strongly needed as these may influence individual treatment selection or sequence.
Following pembrolizumab treatment in melanoma patients, high relative eosinophil count and relative lymphocyte count, low lactate dehydrogenase and absence of metastasis other than those involving the soft tissue/lung were found to be independent baseline characteristics associated with favourable overall survival. 
In fact, the presence of these four factors in combination identifies a subgroup with excellent prognosis.
In contrast, patients with no favourable factors present have poor prognosis.
While not in melanoma, in colorectal cancer positive mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab.
Recent studies have indicated that neoantigen load may form a biomarker in cancer immunotherapy and provide an incentive for the development of novel therapeutic approaches that selectively enhance T cell reactivity against this class of antigens. 
In this regard, the use of a “cancer immunogram” has been proposed.
This tool is based on a number of largely unrelated parameters such as tumour “foreignness” and T cell-inhibitory mechanisms.
Furthermore, the “value” of these parameters can differ greatly between patients. 
For example, in some patients, intratumoural inhibition of tumour-specific T cells will be the sole defect that needs to be addressed, whereas in other patients, the tumour may simply be insufficiently foreign to elicit a clinically relevant T cell response in the first place.
Because of the multifactorial nature of cancer-immune interactions, combinations of biomarker assays will by definition be required.
Several reported have strongly suggested that immune checkpoint blockade therapy leads to upregulation of IFN-γ and in turn clearance of tumour cells. 
IFN-γ plays a dual and opposing role in cancer development.
IFN-γ signalling inhibits tumour growth by arrest of tumour cell cycle, induction of tumour ischaemia and activation of effector cells while impairing suppressive immune cells.
At the same time, it contributes to tumour growth via promotion of tumourigenesis and angiogenesis, upregulation of tolerant molecules and induction of a homeostasis program.
The responses of melanoma to IFN-γ are heterogeneous and frequently downregulated in immune checkpoint inhibitor-naïve melanoma, which could possibly be used as a predictor of response to immunotherapy.
Blocking PD-1 may enhance the durability of anti-tumour responses that are induced by the combined inhibition of BRAF and MEK1.
Over 50% of melanomas harbour various BRAF mutations with the most common being the V600E.
The BRAFV600E mutation gives rise to constitutive activation of the MAPK pathway leading to drug- and/or immune-resistance, apoptosis evasion, proliferation, survival and metastasis of melanomas.
A randomised phase II trial in which patients with treatment-naive BRAFV600E/K-mutant, advanced melanoma received the BRAF inhibitor ‘dabrafenib’ and the MEK inhibitor ‘trametinib’ together with the PD-1-blocking antibody pembrolizumab or placebo. 
Progression-free survival was numerically higher in the triplet group-16.0 months-compared with 10.3 months in the doublet group (HR 0.66; P = 0.043); however, the trial did not reach the planned benefit for statistically significant improvement.
Median duration of response was 18.7 months and 12.5 months (95% confidence interval, 6.0-14.1).
Thus, triplet therapy with dabrafenib, trametinib and pembrolizumab may be a promising treatment strategy that may help to overcome the problem of treatment resistance.
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Müller-Hermelink N, Braumüller H, Pichler B, et al. TNFR1 signaling and IFN-gamma signaling determine whether T cells induce tumor dormancy or promote multistage carcinogenesis. Cancer Cell. 2008 Jun;13(6):507-18.
Ascierto PA, Ferrucci PF, Fisher R, et al. Dabrafenib, trametinib and pembrolizumab or placebo in BRAF-mutant melanoma. Nat Med. 2019 Jun;25(6):941-6.
Presented by: Prof. Kristian Reich, Translational Research in Inflammatory Skin Diseases, Institute for Health Services Research in Dermatology and Nursing, University Medical Center Hamburg-Eppendorf, and Skinflammation® Center, Hamburg, Germany