Until the last decade, chemotherapy was the standard treatment for metastatic cutaneous melanoma, even with poor results. The introduction of immune checkpoints inhibitors (ICIs) radically changed ...the outcome, increasing 5-year survival from 5% to 60%. However, there is still a large portion of unresponsive patients that would need further therapies. NK cells are skin-resident innate cytotoxic lymphocytes that recognize and kill virus-infected as well as cancer cells thanks to a balance between inhibitory and activating signals delivered by surface molecules expressed by the target. Since NK cells are equipped with cytotoxic machinery but lack of antigen restriction and needing to be primed, they are nowadays gaining attention as an alternative to T cells to be exploited in immunotherapy. However, their usage suffers of the same limitations reported for T cells, that is the loss of immunogenicity by target cells and the difficulty to penetrate and be activated in the suppressive tumor microenvironment (TME). Several evidence showed that chemotherapy used in metastatic melanoma therapy possess immunomodulatory properties that may restore NK cells functions within TME. Here, we will discuss the capability of such chemotherapeutics to: i) up-regulate melanoma cells susceptibility to NK cell-mediated killing, ii) promote NK cells infiltration within TME, iii) target other immune cell subsets that affect NK cells activities. Alongside traditional systemic melanoma chemotherapy, a new pharmacological strategy based on nanocarriers loaded with chemotherapeutics is developing. The use of nanotechnologies represents a very promising approach to improve drug tolerability and effectiveness thanks to the targeted delivery of the therapeutic molecules. Here, we will also discuss the recent developments in using nanocarriers to deliver anti-cancer drugs within the melanoma microenvironment in order to improve chemotherapeutics effects. Overall, we highlight the possibility to use standard chemotherapeutics, possibly delivered by nanosystems, to enhance NK cells anti-tumor cytotoxicity. Combined with immunotherapies targeting NK cells, this may represent a valuable alternative approach to treat those patients that do not respond to current ICIs.
Clinical differentiation of progressive supranuclear palsy (PSP) from Parkinson’s disease (PD) is challenging due to overlapping phenotypes and the late onset of specific atypical signs. Therefore, ...easily assessable diagnostic biomarkers are highly needed. Since PD is a synucleopathy while PSP is a tauopathy, here, we investigated the clinical usefulness of serum oligomeric-α-synuclein (o-α-synuclein) and 181Thr-phosphorylated tau (p-tau181), which are considered as the most important pathological protein forms in distinguishing between these two parkinsonisms. We assessed serum o-α-synuclein and p-tau181 by ELISA and SIMOA, respectively, in 27 PSP patients, 43 PD patients, and 39 healthy controls (HC). Moreover, we evaluated the correlation between serum biomarkers and biological and clinical features of these subjects. We did not find any difference in serum concentrations of p-tau181 and o-α-synuclein nor in the o-α-synuclein/p-tau181 ratio between groups. However, we observed that serum p-tau181 positively correlated with age in HC and PD, while serum o-α-synuclein correlated positively with disease severity in PD and negatively with age in PSP. Finally, the o-α-synuclein/p-tau181 ratio showed a negative correlation with age in PD.
Immune checkpoint inhibitors (ICIs) and targeted therapy have dramatically changed the outcome of metastatic melanoma patients. Although immune checkpoints were developed based on the biology of ...adaptive T cells, they have subsequently been shown to be expressed by other subsets of immune cells. Similarly, the immunomodulatory properties of targeted therapy have been studied primarily with respect to T lymphocytes, but other subsets of immune cells could be affected. Innate lymphoid cells (ILCs) are considered the innate counterpart of T lymphocytes and include cytotoxic natural killer cells, as well as three helper subsets, ILC1, ILC2 and ILC3. Thanks to their tissue distribution and their ability to respond rapidly to environmental stimuli, ILCs play a central role in shaping immunity. While the role of NK cells in melanoma physiopathology and therapy is well established, little is known about the other helper ILC subsets. In this review, we summarize recent findings on the ability of the melanoma TME to influence the phenotype and functional plasticity of helper ILCs and highlight how this subset may in turn shape the TME. We also discuss changes in the melanoma TME induced by targeted therapy that could affect helper ILC functions, the expression of immune checkpoints on this subset and how their inhibition by ICIs may modulate helper ILC function and contribute to therapeutic efficacy.
The ability of pathogens to sequester iron from their host cells and proteins affects their virulence. Moreover, iron is required for various innate host defense mechanisms as well as for acquired ...immune responses. Therefore, intracellular iron concentration may influence the interplay between pathogens and immune system. Here, we investigated whether changes in iron concentrations and intracellular ferritin heavy chain (FTH) abundance may modulate the expression of Major Histocompatibility Complex molecules (MHC), and susceptibility to Natural Killer (NK) cell cytotoxicity. FTH downregulation, either by shRNA transfection or iron chelation, led to MHC surface reduction in primary cancer cells and macrophages. On the contrary, mouse embryonic fibroblasts (MEFs) from NCOA4 null mice accumulated FTH for ferritinophagy impairment and displayed MHC class I cell surface overexpression. Low iron concentration, but not FTH, interfered with IFN-γ receptor signaling, preventing the increase of MHC-class I molecules on the membrane by obstructing STAT1 phosphorylation and nuclear translocation. Finally, iron depletion and FTH downregulation increased the target susceptibility of both primary cancer cells and macrophages to NK cell recognition. In conclusion, the reduction of iron and FTH may influence the expression of MHC class I molecules leading to NK cells activation.
Monoclonal antibodies targeting immune checkpoints improved clinical outcome of patients with malignant melanoma. However, the mechanisms are not fully elucidated. Since immune check-point receptors ...are also expressed by helper innate lymphoid cells (ILCs), we investigated the capability of immune checkpoints inhibitors to modulate ILCs in metastatic melanoma patients as well as melanoma cells effects on ILC functions. Here, we demonstrated that, compared to healthy donors, patients showed a higher frequency of total peripheral ILCs, lower percentages of CD117
ILC2s and CD117
ILCs as well as higher frequencies of CD117
ILCs. Functionally, melanoma patients also displayed an impaired TNFα secretion by CD117
ILCs and CD117
ILCs. Nivolumab therapy reduced the frequency of total peripheral ILCs but increased the percentage of CD117
ILC2s and enhanced the capability of ILC2s and CD117
ILCs to secrete IL-13 and TNFα, respectively. Before Nivolumab therapy, high CCL2 serum levels were associated with longer Overall Survival and Progression Free Survival. After two months of treatment, CD117
ILC2s frequency as well as serum concentrations of IL-6, CXCL8 and VEGF negatively correlated with both the parameters. Moreover, melanoma cells boosted TNFα production in all ILC subsets and increased the number of IL-13 producing ILC2s
. Our work shows for the first time that PD-1 blockade is able to affect ILCs proportions and functions in melanoma patients and that a specific subpopulation is associated with the therapy response.
The growth and recurrence of a number of cancers is driven by a scarce population of cancer stem cells (CSCs), which are resistant to most current therapies. It has been shown previously that natural ...killer (NK) cells recognize human glioma, melanoma, colon and prostate CSCs
. We herein show that human and mouse breast CSCs are also susceptible to NK cytotoxic activity
. Moreover, CSC induced autologous NK cell activation and expansion
, which correlate with the inhibition of CSC metastatic spread. These data suggest that NK cells control CSC metastatic spread
and that their use in breast cancer therapy may well be fruitful.
Fibromyalgia (FM) is a serious chronic pain syndrome, characterised by muscle and joint stiffness, insomnia, fatigue, mood disorders, cognitive dysfunction, anxiety, depression and intestinal ...irritability. Irritable Bowel Syndrome (IBS) shares many of these symptoms, and FM and IBS frequently co-exist, which suggests a common aetiology for the two diseases. The exact physiopathological mechanisms underlying both FM and IBS onset are unknown. Researchers have investigated many possible causes, including alterations in gut microbiota, which contain billions of microorganisms in the human digestive tract. The gut-brain axis has been proven to be the link between the gut microbiota and the central nervous system, which can then control the gut microbiota composition. In this review, we will discuss the similarities between FM and IBS. Particularly, we will focus our attention on symptomatology overlap between FM and IBS as well as the similarities in microbiota composition between FM and IBS patients. We will also briefly discuss the potential therapeutic approaches based on microbiota manipulations that are successfully used in IBS and could be employed also in FM patients to relieve pain, ameliorate the rehabilitation outcome, psychological distress and intestinal symptoms.
Immune checkpoint blockade therapy has changed prognoses for many melanoma patients. However, immune responses that correlate with clinical progression of the disease are still poorly understood. To ...identify immune responses correlating with melanoma clinical evolution, we analyzed serum cytokines as well as circulating NK and T-cell subpopulations from melanoma patients. The patients' immune profiles suggested that melanoma progression leads to changes in peripheral blood NK and T-cell subsets. Stage IV melanoma was characterized by an increased frequency of CCR7
CD56
NK cells as well as high serum concentrations of the CCR7 ligand CCL19. CCR7 expression and CCL19 secretion were also observed in melanoma cell lines. The CCR7
melanoma cell subpopulation coexpressed PD-L1 and Galectin-9 and had stemness properties. Analysis of melanoma-derived cancer stem cells (CSC) showed high CCR7 expression; these CSCs were efficiently recognized and killed by NK cells. An accumulation of CCR7
, PD-L1
, and Galectin-9
melanoma cells in melanoma metastases was demonstrated
Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.
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