Overcoming Immune Evasion in Melanoma

Abstract

Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is “curable” at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease.

The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

“…However, althoughtreatment with anti-PD-1/PD-L1 inhibitors yields unprecedented clinical effects, a consistent number of patients ranging from 40% to 60% are refractory to the therapy and/or experience severe adverse events [ 5 ]. Multiple studies have investigated the levels of PD-L1 expression and the activity of intratumoral immune effector cells as predictive biomarkers of therapy response, yet they have failed to efficiently identify the fraction of patients which do not respond to the treatments [ 6 , 7 ]. Thus, there is the need to better clarify the molecular mechanisms regulating the PD-1/PD-L1 pathway and to develop new prognostic and predictive biomarkers.…”

Decoding Melanoma Development and Progression: Identification of Therapeutic Vulnerabilities

“…The concept of immunotherapy has been around for approximately 130 years with the early usage of Coley’s toxin, then almost a century later, the uses of interferon (IFN), high dose interleukin- 2 (IL-2) and the cancer vaccine, Bacillus-Calmette-Guerin (BCG) have been described for the treatment of melanoma ( 151 – 153 ). These early immunotherapies were non-specific, however within the past decade the utilization of targeted immunotherapies have risen with monoclonal antibodies that block immune checkpoint molecules, such as cytotoxic T-lymphocyte associated protein–4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed death ligand-1 (PD-L1), adoptive T-cell therapies and oncolytic viruses ( 151 , 153 – 155 ). These new targeted immunotherapies have shown remarkable anti-tumor immune responses with improved survival; however, they only benefit a subset of patients.…”

“…Patients who harbor mutated BRAF are given adjuvant anti-PD-1 therapy in combination with BRAF and MEK inhibitors, while patients with wild-type BRAF are given anti-PD-1, as opposed to anti-CTLA-4 due to toxicity ( 170 ). The anti-PD-L1 antibody, Atezolizumab has been approved for unresectable or metastatic melanoma patients with the BRAF V600 mutation in combination with BRAF and MEK inhibitors, Vemurafenib and Cobimetinib ( 153 ). It is not surprising that various combinatorial studies utilizing various permutations of drugs to combine with anti-PD-1/anti-PD-L1 may improve patients’ responsiveness to immune checkpoint blockade therapy have been one of the most sought-after clinical trials in human cancers including melanoma ( 169 ).…”

Unraveling the Wide Spectrum of Melanoma Biomarkers

“…It is estimated that melanoma will be the 19th most common worldwide primary site of new cancers in both sexes in 2020, with 324,635 cases [1]. Very recently, immune evasion by cancer cells has become an important therapeutic target [2]. The prognosis varies according to the stage of the disease, from almost 99% 5-year survival rate in localised disease to approximately 27% when distant metastases are present [3].…”