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.

Despite the success of immune checkpoint blockade in melanoma, the majority of patients do not respond. We hypothesized that the T and NK cell subset frequencies and expression levels of their receptors may predict responses and clinical outcome of anti-CTLA-4 treatment. We thus characterized the NK and T cell phenotype, as well as serum levels of several cytokines in 67 melanoma patients recruited in Italy and Sweden, using samples drawn prior to and during treatment. Survival correlated with low expression of the inhibitory receptor TIM-3 on circulating T and NK cells prior to and during treatment and with the increased frequency of mature circulating NK cells (defined as CD3⁻CD56^dim CD16⁺) during treatment. Survival also correlated with low levels of IL-15 in the serum. Functional experiments in vitro demonstrated that sustained exposure to IL-15 enhanced the expression of PD-1 and TIM-3 on both T and NK cells, indicating a causative link between high IL-15 levels and enhanced expression of TIM-3 on these cells. Receptor blockade of TIM-3 improved NK cell-mediated elimination of melanoma metastasis cell lines in vitro. These observations may lead to the development of novel biomarkers to predict patient response to checkpoint blockade treatment. They also suggest that induction of additional checkpoints is a possibility that needs to be considered when treating melanoma patients with IL-15.

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.

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 in vitro. We herein show that human and mouse breast CSCs are also susceptible to NK cytotoxic activity in vitro. Moreover, CSC induced autologous NK cell activation and expansion in vivo, which correlate with the inhibition of CSC metastatic spread. These data suggest that NK cells control CSC metastatic spread in vivo and that their use in breast cancer therapy may well be fruitful.

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+CD56bright 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 ex vivo. Altogether, our data identify biomarkers that may mark a CCR7-driven metastatic melanoma pathway.

In humans, NK cells are mainly identified by the surface expression levels of CD56 and CD16, which differentiate between five functionally different NK cell subsets. However, nowadays NK cells are considered as a more heterogeneous population formed by various subsets differing in function, surface phenotype and anatomic localization. In HCMV- and hantaviruses-infected subjects, an increased frequency of a NKG2A- CD57+ NKG2C+ NK cell subset has been observed, while the phenotype of the NK cell subpopulation associated with cancer may vary according to the specific kind of tumor and its anatomical location. The healthy human lymph nodes contain mainly the CD56bright NK cell subset while in melanoma metastatic lymph nodes the CD56dimCD57+KIR+ CCR7+ NK cell subpopulation prevails. The five NK cell subpopulations are found in breast cancer patients, where they differ for expression pattern of chemokine receptors, maturation stage functional capabilities. In pregnancy, uterine NK cells show a prevalence of the CD56brightCD16- NK cell compartment, whose activity is influenced by KIRs repertoire. This NK cell subset’s super specialization could be explained by i) the expansion of single mature CD56dim clones, ii) the recruitment and maturation of CD56bright NK cells through specific stimuli, iii) the in situ development of tumor-resident NK cells from tissue-resident CD56bright NK cells independently of the circulating NK cell compartment. This new and unexpected biological feature of the NK cell compartment could be an important source of new biomarkers to improve patients’ diagnosis.