biomedicines Review Metabolic Interplay between the Immune System and Melanoma Cells: Therapeutic Implications Alice Indini 1 , Francesco Grossi 2, Mario Mandalà 3, Daniela Taverna 4 and Valentina Audrito 4,* 1 Medical Oncology Unit, Department of Internal Medicine, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy; [email protected] 2 Medical Oncology Unit, Department of Medicine and Surgery, University of Insubria, ASST dei Sette Laghi, 21100 Varese, Italy; [email protected] 3 Unit of Medical Oncology, Santa Maria Misericordia Hospital, University of Perugia, 06156 Perugia, Italy; [email protected] 4 Molecular Biotechnology Center, Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; [email protected] * Correspondence: [email protected] Abstract: Malignant melanoma represents the most fatal skin cancer due to its aggressive biological behavior and high metastatic potential. Treatment strategies for advanced disease have dramatically changed over the last years due to the introduction of BRAF/MEK inhibitors and immunotherapy. However, many patients either display primary (i.e., innate) or eventually develop secondary (i.e., acquired) resistance to systemic treatments. Treatment resistance depends on multiple mechanisms driven by a set of rewiring processes, which involve cancer metabolism, epigenetic, gene expression, and interactions within the tumor microenvironment. Prognostic and predictive biomarkers are needed to guide patients’ selection and treatment decisions. Indeed, there are no recognized clinical or biological characteristics that identify which patients will benefit more from available treatments, Citation: Indini, A.; Grossi, F.; Mandalà, M.; Taverna, D.; Audrito, V. but several biomarkers have been studied with promising preliminary results. In this review, we will Metabolic Interplay between the summarize novel tumor metabolic pathways and tumor-host metabolic crosstalk mechanisms leading Immune System and Melanoma Cells: to melanoma progression and drug resistance, with an overview on their translational potential as Therapeutic Implications. novel therapeutic targets. Biomedicines 2021, 9, 607. https:// doi.org/10.3390/biomedicines9060607 Keywords: melanoma; metabolic reprogramming; immunometabolism; soluble factors; tumor microenvironment; targeted therapy; immunotherapy Academic Editors: Cristina M. Failla and Eleonora Candi Received: 27 April 2021 1. Introduction Accepted: 25 May 2021 Published: 26 May 2021 Cutaneous melanoma represents 5.6% of all new cancer cases in the United States (US) [1]. According to the Surveillance, Epidemiology, and End Results (SEER) database, Publisher’s Note: MDPI stays neutral the 5-year relative survival rate for patients with cutaneous melanoma (all stages) exceeds with regard to jurisdictional claims in 93%, ranging from 99% for localized and early-stage disease to less than 30% for metastatic published maps and institutional affil- disease [1]. Over the last years, the prognosis of patients with advanced/metastatic iations. melanoma has significantly improved with the introduction of novel therapeutic strategies. These include drugs targeting the mitogen activated protein-kinase (MAPK) pathway, namely, BRAF and MEK inhibitors, in patients with BRAF mutant melanoma (i.e., approxi- mately 50% of patients with cutaneous melanoma) [2,3]. To date, three different targeted therapies against BRAF and MEK have been approved for the treatment of advanced Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. unresectable/metastatic melanoma, namely, vemurafenib plus cobimetinib, dabrafenib This article is an open access article plus trametinib, and encorafenib plus binimetinib [2–4]. The combination of dabrafenib distributed under the terms and and trametinib has recently demonstrated to provide sustained relapse-free survival im- conditions of the Creative Commons provement as an adjuvant treatment for resected stage III melanoma, thus, being approved Attribution (CC BY) license (https:// in this therapeutic setting [5]. creativecommons.org/licenses/by/ Another therapeutic strategy consists of the use of monoclonal antibodies targeting 4.0/). immune checkpoint molecules, such as the anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) Biomedicines 2021, 9, 607. https://doi.org/10.3390/biomedicines9060607 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 23 Another therapeutic strategy consists of the use of monoclonal antibodies targeting immune checkpoint molecules, such as the anti-cytotoxic T-lymphocyte antigen 4 (CTLA- 4) antibody, ipilimumab, and the anti-programmed cell death 1 (PD-1) antibodies, Biomedicines 2021nivolumab, 9, 607 and pembrolizumab [6–9]. Given the survival advantages with a more favor-2 of 23 able toxicity profile, anti-PD1 treatment has become the standard first line immunother- apy strategy, while anti-CTLA-4 is commonly used in further lines of treatment in case of disease progressionantibody, on previous ipilimumab, anti and-PD1 the anti-programmed therapy. The cellcombination death 1 (PD-1) of antibodies,ipilimumab nivolumab plus nivolumab has demonstratedand pembrolizumab to provide [6–9]. Given further the survival improvements advantages in with survival a more outcomes, favorable toxicity also in challenging subpopulationsprofile, anti-PD1 treatmentof patients has (e.g. become, patients the standard with firstbrain line metastases), immunotherapy however strategy,, with a higher ratewhile of immune anti-CTLA-4-related is commonly adverse used events in further [8]. linesAnti of-PD1 treatment treatment in case has of disease recent pro-ly gression on previous anti-PD1 therapy. The combination of ipilimumab plus nivolumab become standardhas of demonstrated care in the adjuvant to provide setting further improvementsfor patients with in survival resected outcomes, stage alsoIII (pem- in chal- brolizumab or nivolumab)lenging subpopulations or stage IV of melanoma patients (e.g., with patients no withevidence brain metastases),of disease (nivolumab) however, with a [10,11]. higher rate of immune-related adverse events [8]. Anti-PD1 treatment has recently become Despite thestandard undoubted of care therapeutic in the adjuvant advances, setting for the patients majority with resectedof patients stage with III (pembrolizumab metastatic or nivolumab) or stage IV melanoma with no evidence of disease (nivolumab) [10,11]. melanoma will still Despitedie from the their undoubted disease, therapeutic either advances,because theof majorityprimary of (i.e. patients, innate) with metastatic or sec- ondary (i.e., acquired/adaptive)melanoma will still resistance die from their mechanisms disease, either (Figure because 1) of [12 primary–14]. (i.e.,Several innate) differ- or sec- ent predictive andondary prognostic (i.e., acquired/adaptive) biomarkers have resistance been mechanisms investigated (Figure to1 improve)[ 12–14]. Severalpatients’ different se- lection and risk predictivestratification, and prognostic however biomarkers, with disappointing have been investigated and inconsistent to improve results patients’ [15 selec-– 18]. Intense researchtion and is, risktherefore stratification,, required however, to understand with disappointing the biologic and inconsistent and molecularresults [15 fea-–18]. Intense research is, therefore, required to understand the biologic and molecular features of tures of aggressiveaggressive melanoma melanoma and and the the mec mechanismshanisms underlying underlying treatment treatment resistance resistance [13] to increase [13] to increase therapeutictherapeutic possibilities. possibilities. Figure 1. Role of the mitogen activated protein kinase (MAPK) pathway in melanoma cells and Figure 1. Role of the mitogen activated protein kinase (MAPK) pathway in melanoma cells and targets of BRAF and MEK inhibitors.targets In normal of BRAF cells, and external MEK growth inhibitors. stimuli triggerIn normal receptor cells, tyrosine external kinase growth (RTK), activatingstimuli trigger the MAPK receptor pathway tyro- kinasesine cascade. kinase In BRAF-driven (RTK), activating melanoma, the mutantMAPK BRAF pathway (BRAF kinaseV600E) cascade. can start signalingIn BRAF independently-driven melanoma, of growth mu- factortant signal BRAF to hyperactivate (BRAF V600E) cellular can growth. start signaling BRAF mutated independently melanoma responds of growth to BRAF/MEK factor signal inhibitors-targeted to hyperactivate therapy.cellular However, growth. various BRAF intrinsic mutated or adaptive melanoma resistance mechanisms responds attenuateto BRAF/MEK response toinhibitors targeted BRAF-targeted inactivation, therapy. deregulatingHowever, signaling various and rewiring intrinsic cell or metabolism. adaptive resistance mechanisms attenuate response to targeted BRAF inactivation, deregulating signaling and rewiring cell metabolism. Metabolic rewiring (i.e., glycolysis and/or oxidative phosphorylation OXPHOS path- ways) in melanoma, and the metabolic crosstalk between melanoma cells and the com- Metabolic rewiringponents of (i.e. the, tumor glycolysis microenvironment and/or oxidat (TME),ive phosphorylation represent an intriguing OXPHOS field of research path- ways) in melanoma, and the metabolic crosstalk between melanoma cells and the compo- nents of the tumor microenvironment (TME), represent an intriguing field of research due Biomedicines 2021, 9, 607 3 of 23 due to the role of metabolic