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Nanomedicines As Multifunctional Modulators of Melanoma Immune Microenvironment

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Nanomedicines As Multifunctional Modulators of Melanoma Immune Microenvironment REVIEW www.advtherap.com Nanomedicines as Multifunctional Modulators of Melanoma Immune Microenvironment Barbara Carreira, Rita C. Acúrcio, Ana I. Matos, Carina Peres, Sabina Pozzi, Daniella Vaskovich-Koubi, Ron Kleiner, Mariana Bento, Ronit Satchi-Fainaro,* and Helena F. Florindo* these tumors. New treatments approved Melanoma is the most destructive and deadly among skin cancers. Patients over the last decade have improved the sur- presenting the most disseminated form of this disease have very low survival vival of patients with melanoma, but the rates (≈15%) and highly restricted therapeutic alternatives. In recent years, global incidence rate of this disease is con- [1] the area of cancer immunotherapy has witnessed remarkable developments stantly rising. Melanoma is potentially treatable when in the management of many cancers, including melanoma. In fact, diagnosed at early stages. However, the immunotherapy unveiled as a feasible therapeutic alternative for late-stage prognosis of patients suffering from the melanoma patients, specifically using immune checkpoint therapies. advanced stage of this disease is highly However, despite the exciting outcomes, only a small percentage of patients limited. In this situation, melanoma com- respond to these therapies, and severe immune-related adverse reactions monly spreads to the lungs, gastrointesti- have been often reported. As such, most of preclinical and clinical studies nal tract, skin, and brain. Melanoma brain metastases constitute the third most com- currently explore melanoma tumor biology and immunology to guide the mon cause of intracranial tumors, affect- development of combinational immunotherapies aiming at relevant clinical ing around 10% of patients with ma- efficacy and minimal toxicity. Herein, the current knowledge on melanoma lignant melanoma, who usually have a biology and immunology is discussed, focusing on nanotechnology as a median survival of less than 4 months. crucial strategy for the development of combinatorial approaches able to Current melanoma treatment options are based on tumor stage and localiza- specifically modulate the function of key players responsible for melanoma tion. Therapeutic approaches available for evolution and evasion of host immune-mediated attacks. Finally, the major this disease include surgery, for the exci- challenges toward the clinical implementation of these emergent targeted sion of the lesions, radiation, chemother- nanomedicines for immunotherapy are further discussed, with particular apy, and targeted therapies. In the last focus on melanoma genomics, predictive biomarkers, clinical trial design, and few years, advanced knowledge has been clinical regulation of nanomedicines. generated about melanoma immune mi- croenvironment, revealing the dynamic in- teraction between tumor, immune, and stromal cells. Immunotherapeutic-based 1. Introduction strategies constitute the new fourth pillar of cancer healthcare, being directed to the regulation of these tumor specific immune- Melanoma is a malignancy of melanocytes and represents 1% mediated pathways and targets, aiming at an improved efficacy, of skin cancers, being the most aggressive and lethal among while overcoming toxicity due to off-target effects. Checkpoint blockade therapy using monoclonal antibodies (mAb) against cytotoxic T lymphocyte-associated antigen 4 B. Carreira, Dr. R. C. Acúrcio, Dr. A. I. Matos, Dr. C. Peres, M. Bento, (CTLA-4) or programmed cell death 1 (PD-1)/programmed cell- Prof. H. F. Florindo ligand 1 (PD-L1) has indeed led to durable responses, as a Research Institute for Medicines (iMed.ULisboa) [2] Faculty of Pharmacy, University of Lisbon monotherapy or in combination. However, a significant part Av. Prof. Gama Pinto, Lisboa 1649-003, Portugal of individuals affected by the disseminated form of melanoma E-mail: hflorindo@ff.ulisboa.pt fails to develop a therapeutic response to these checkpoint in- S. Pozzi, D. Vaskovich-Koubi, R. Kleiner, Prof. R. Satchi-Fainaro hibitors, often acquiring resistance to these therapies.[3] There- Department of Physiology and Pharmacology, Sackler Faculty of Medicine fore, despite these exciting breakthroughs, the discovery and de- Tel Aviv University Tel Aviv 6997801, Israel velopment of new alternative immunotherapeutic options and/or E-mail: [email protected] combinations are urgently needed to promote effectiveness and patient response rates. The ORCID identification number(s) for the author(s) of this article Recent developments in the fields of nanotechnology, chem- can be found under https://doi.org/10.1002/adtp.202000147 ical biology, biotechnology, as well as tumor immunology and DOI: 10.1002/adtp.202000147 biology, are opportune to address this unmet medical need by Adv. Therap. 2020, 2000147 2000147 (1 of 39) © 2020 Wiley-VCH GmbH www.advancedsciencenews.com www.advtherap.com enabling the rational design of new strategies to target spe- cific cancer aggressiveness-related pathways, while regulating the function of tumor immune evasion-associated players.[4] This re- view discusses the potential of nanomedicines to target and mod- ulate the function and frequency of multiple key players of the melanoma microenvironment to overcome tumor immune eva- sion, and thereby dramatically improve the safety and efficacy of immunotherapies against advanced/metastatic melanoma. Im- portantly, it will discuss the major challenges toward the clini- cal implementation of these emerging nanotechnology-based im- munotherapies. 2. Concept of Immunology in Cancer The modulation of host immune response toward the destruc- tion of cancer cells is a major topic within biomedical science. It is now widely accepted that the host immune system can iden- tify and eliminate malignant cells. However, while progressing, cancer cells develop mechanisms to escape immunosurveillance barriers.[5] The Chen and Mellman cancer-immunity cycle[6] nicely addresses this complex immune response induced against cancer. This immunoediting theory includes three intercon- Figure 1. Melanoma and host immune system interactions. Natural killer nected phases: i) immunosurveillance-mediated cancer cell elim- (NK) cells have distinct inhibitory and activating receptors, whose sig- ination; ii) equilibrium resultant from the cancer-immune cell nals control the active state of these innate immune system cells. Once activated, for example, following their binding to tumor-related ligands, interplay; and iii) immune escape. The transition between these NK cells release cytotoxic molecules that will cause the destruction of phases is adjusted by tumor cells’ activity and the immune sys- those malignant cells, in addition to cytokines that will attract dendritic tem status.[7] cells (DC) and other phagocytes. These will recognize and capture tumor During elimination, the first stage of the cancer-immunity cy- cells, further presenting their tumor-associated antigens (TAA) to T and cle, both innate and adaptive arms of the immune system act in B cells, thus leading to the activation of the adaptive arm of the immune a concerted manner to recognize and destroy tumor cells. This is system. Cytotoxic granules will be released from cytotoxic T cells (CTL) at tumor cell surface once the T cell receptor (TCR) of CD8+ T cells recognize a process based on two distinct but interconnected phases. The the TAA bound to major histocompatibility complex (MHC) molecules on first fast-nonspecific early response is driven by the innate arm of DC surface. CD4+ T cells that recognize TAA-MHC class II complex on the immune system, which includes the involvement of dendritic the surface of these antigen-presenting cells (APC), will further activate B cells (DCs), macrophages, natural killer (NK) cells, and granu- cells, leading to the release of tumor-specific antibodies. The cells of the locytes. A late phase encompasses the recognition and further adaptive immune system will reactivate the function of the innate immu- internalization of tumor-associated antigens (TAA) by antigen- nity components via receptor/ligand systems, soluble factors, as cytokines and chemokines, and/or increased amounts of antigens that are released presenting cells (APCs), primarily DC, being processed and sub- following tumor cell death. Adapted with permission.[11] Copyright 2019, sequently loaded into major histocompatibility complex (MHC) Elsevier. molecule and subsequently presented to T-lymphocyte popula- tions in the lymph nodes (Figure 1). In this phase, CD8+ ef- fector T lymphocytes are the major players in tumor cell clear- ance, assisted and complemented by various other populations of immune cells, including NK, CD4+ effector T cells, as well immunity-mediated events. However, tumor cells gradually as B cells, which act together either within tumor microenviron- downregulate the expression of MHC class I and MHC class II ment (TME) or at the peripheral tissues to effectively eliminate all molecules, blocking the binding of antigens, which will then be melanoma cells.[5a] Once the elimination phase is accomplished, released in high quantities. However, during this phase, the tu- malignant cells are eradicated before they become clinically de- mor cells are subjected to a constant selected immune pressure, tectable cancers, constituting an endpoint for the immunoediting and those malignant cells with higher ability to evade this con- process.[5b,8] trol, will escape and become a clinically relevant disorder.[9] This The equilibrium phase or tumor dormancy period results from tumor immune evasion constitutes
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