The complex relationship between MITF and the immune system: a Melanoma ImmunoTherapy (response) Factor? Robert Ballotti, Yann Cheli, Corine Bertolotto To cite this version: Robert Ballotti, Yann Cheli, Corine Bertolotto. The complex relationship between MITF and the im- mune system: a Melanoma ImmunoTherapy (response) Factor?. Molecular Cancer, BioMed Central, 2020, 19 (1), pp.170. 10.1186/s12943-020-01290-7. inserm-03138744 HAL Id: inserm-03138744 https://www.hal.inserm.fr/inserm-03138744 Submitted on 11 Feb 2021 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Ballotti et al. Molecular Cancer (2020) 19:170 https://doi.org/10.1186/s12943-020-01290-7 REVIEW Open Access The complex relationship between MITF and the immune system: a Melanoma ImmunoTherapy (response) Factor? Robert Ballotti1,2, Yann Cheli1,2 and Corine Bertolotto1,2* Abstract The clinical benefit of immune checkpoint inhibitory therapy (ICT) in advanced melanomas is limited by primary and acquired resistance. The molecular determinants of the resistance have been extensively studied, but these discoveries have not yet been translated into therapeutic benefits. As such, a paradigm shift in melanoma treatment, to surmount the therapeutic impasses linked to the resistance, is an important ongoing challenge. This review outlines the multifaceted interplay between microphthalmia-associated transcription factor (MITF), a major determinant of the biology of melanoma cells, and the immune system. In melanomas, MITF functions downstream oncogenic pathways and microenvironment stimuli that restrain the immune responses. We highlight how MITF, by controlling differentiation and genome integrity, may regulate melanoma-specific antigen expression by interfering with the endolysosomal pathway, KARS1, and antigen processing and presentation. MITF also modulates the expression of coinhibitory receptors, i.e., PD-L1 and HVEM, and the production of an inflammatory secretome, which directly affects the infiltration and/or activation of the immune cells. Furthermore, MITF is also a key determinant of melanoma cell plasticity and tumor heterogeneity, which are undoubtedly one of the major hurdles for an effective immunotherapy. Finally, we briefly discuss the role of MITF in kidney cancer, where it also plays a key role, and in immune cells, establishing MITF as a central mediator in the regulation of immune responses in melanoma and other cancers. We propose that a better understanding of MITF and immune system intersections could help in the tailoring of current ICT in melanomas and pave the way for clinical benefits and long-lasting responses. Treatments and resistance to treatments in forms which have the greatest impact on mortality has melanoma remained stable. Prior to 2011, no treatment has demon- Cutaneous melanoma is a malignant tumor that de- strated a significant impact on the overall survival of pa- velops from melanocytes and affects patients of all ages. tients with metastatic melanoma. The global incidence in 2015 was estimated to be 350, The first therapeutic revolution in the management of 000, new cases [1] and is constantly increasing while the melanomas followed the discovery of activating muta- V600E mortality is stable or in discrete increase [2]. The in- tions in BRAF (mainly BRAF ) in approximately 50% creased incidence is probably due to the improved early of melanomas in 2002 [3]. BRAFV600E has also been detection of thin forms, while the incidence of thicker identified in papillary thyroid cancer, non-small cell lung cancer, colorectal cancers and serous ovarian carcinoma. V600E * Correspondence: [email protected] Vemurafenib and dabrafenib, specific BRAF inhibi- 1 Université Côte d’Azur, Nice, France tors, that do not inhibit wild type BRAF, were the first 2Inserm, Biology and Pathologies of melanocytes, team1, Equipe labellisée Ligue 2020 and Equipe labellisée ARC 2019, Centre Méditerranéen de targeted therapies used in metastatic melanoma which Médecine Moléculaire, Nice, France produced a spectacular response rate of 60% for the first © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. 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However, secondary resistance develops within a few A substantial amount of work has led to the identifica- months, resulting in a poor increase in median tion of the mechanisms of resistance to ICT in melano- progression-free survival (5 to 7 months) with BRAFV600E mas and, more generally, solid cancers (for review see inhibitor treatment [4]. A combination of BRAFV600E and [14, 15]. In brief, resistance can be ascribed to (i) a poor MEK inhibitors, which is now the standard of care, gives immunogenicity of the tumor, due to defective antigen rise to a better response rate that reaches 75% [5] and de- expression or presentation in a context impairing im- lays the onset of resistance. Combination therapies there- mune cell activation, (ii) an altered T-cell trafficking to fore significantly prolonged median overall survival (up the tumor and (iii) reduced T-cell killing activity within 25 months) and median progression-free survival (PFS) up the tumor. All these effects are mediated mainly by the to 12 months [6]. Despite this, resistance still occurs and tumor itself, but also by the tumor microenvironment worsens the clinical outcome of patients. (inflammation, hypoxia composition, matrix make-up, The second paradigm shift in melanoma treatment nutrient availability, etc.), composition of the immune came from the use of monoclonal antibodies preventing infiltrate and by long-distance signaling arising from the the engagement of CTLA4 (Cytotoxic T-lymphocyte- gut microbiota. Associated protein 4) or PD1 (Programmed Death pro- tein 1), which are coinhibitory receptors expressed on Pivotal role of MITF in the response of melanoma the surface of T cells [7], with their ligands expressed on to immunotherapies the surface of tumor cells. Anti-CTLA4 and anti-PD1 Here, we focus our attention on intrinsic and melanoma immune checkpoint inhibitor therapies (ICTs) prevent specific mechanisms that could account for ICT therapy immune cell exhaustion and stimulate immune re- resistance and that would be amenable targets for new sponses against tumor cells. therapeutic strategies. Melanoma-specific mechanisms ICT has revolutionized the treatment of patients with almost universally involve the MIcrophthalmia- cancer, to such an extent that Professors James Allison associated Transcription Factor (MITF). MITF com- and Tasuko Honjo were awarded the 2018 Nobel Prize prises eight isoforms differentially expressed within vari- in Physiology or Medicine for their discovery of cancer ous cell types and tissues [16]. The MITF-M isoform therapy focused on inhibition of negative immune regu- (hereafter simply designated as MITF) is the master lation. Adoptive T-cell therapy (ACT) can also induce regulator of melanocytes and has been identified as an durable antitumor responses due to the lasting memory addictive oncogene in melanoma [17–20]. feature of the adaptive immune system [8]. Interleukin 2 The leading hypothesis in the field is that high MITF (IL-2), interferon, and oncolytic viral therapies can also expression (MITFhigh) is associated with a differentiated have clinical benefits in melanoma, and they stand as al- and proliferative phenotype, whereas low MITF expres- ternatives for a subset of patients [9, 10]. sion (MITFlow), is associated with a dedifferentiated, in- ICTs have significantly improved outcomes for vasive, apoptosis-resistant, and melanoma-initiating cell advanced-stage melanoma patients [11]. ICT agents phenotype [21]. MITFhigh and MITFlow cells coexist in show less impressive overall response rates (40% for melanoma tumors [22–24], and can originate from a re- anti-PD1 therapy and 20% for anti-CTLA4 therapy) than versible phenotypic switch that is responsible for melan- targeted therapies, while when combined they reach a oma plasticity and intratumor heterogeneity [25]. Signals