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The immunophenotype of oldest centenarians, i.e., semi- and supercentenarians, could provide important information about their ability to adapt to factors associated with immune changes, including ageing per se and chronic Cytomegalovirus infection. We investigated, by flow cytometry, variations in percentages and absolute numbers of immune cell subsets, focusing on T cells, and pro-inflammatory parameters in a cohort of 28 women and 26 men (age range 19-110 years). We observed variability in hallmarks of immunosenescence related to age and Cytomegalovirus serological status. The eight oldest centenarians showed the lowest percentages of naïve T cells, due to their age, and the highest percentages of T effector memory cells re-expressing CD45RA (TEMRA), according to their Cytomegalovirus status, and high levels of serum pro-inflammatory parameters, although their means were lower than that of remaining 90+ donors. Some of them showed CD8 naïve and TEMRA percentages, exhaustion/pro-inflammatory markers comparable to the younger ones. Our study supports the suggestion that immune ageing, especially of oldest centenarians, exhibits great variability that is not attributable to a single contributor, but should be the full result of a combination of several factors. Everyone ages differently because he/she is unique in genetics and experience of life and this applies even more to the immune system; everybody has had a different immunological history. Furthermore, our findings on inflammatory markers, TEMRA and CMV seropositivity in centenarians, discussed in the light of the most recent literature, suggest that these changes might be not unfavourable for centenarians, and in particular for the oldest ones.

Supplemental Material for Autologous conditioned serum for chronic pain in patients with osteoarthritis: A feasibility observational study by Mariachiara Ippolito, Giulia Spurio, Viviana Compagno, Alessandra Rizzo, Marta Di Simone, Anna Maria Corsale, Giuseppina Mazzola, Antonino Giarratano, Serena Meraviglia, Andrea Cortegiani, and Antonietta Alongi in British Journal of Pain

Multiple myeloma (MM) is an incurable hematologic malignancy characterized by a multistep evolutionary pathway, with an initial phase called monoclonal gammopathy of undetermined significance (MGUS), potentially evolving into the symptomatic disease, often preceded by an intermediate phase called “smoldering” MM (sMM). From a biological point of view, genomic alterations (translocations/deletions/mutations) are already present at the MGUS phase, thus rendering their role in disease evolution questionable. On the other hand, we currently know that changes in the bone marrow microenvironment (TME) could play a key role in MM evolution through a progressive shift towards a pro-inflammatory and immunosuppressive shape, which may drive cancer progression as well as clonal plasma cells migration, proliferation, survival, and drug resistance. Along this line, the major advancement in MM patients’ survival has been achieved by the introduction of microenvironment-oriented drugs (including immunomodulatory drugs and monoclonal antibodies). In this review, we summarized the role of the different components of the TME in MM evolution from MGUS as well as potential novel therapeutic targets/opportunities.

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In recent years, research has focused on colorectal cancer to implement modern treatment approaches to improve patient survival. In this new era, γδ T cells constitute a new and promising candidate to treat many types of cancer because of their potent killing activity and their ability to recognize tumor antigens independently of HLA molecules. Here, we focus on the roles that γδ T cells play in antitumor immunity, especially in colorectal cancer. Furthermore, we provide an overview of small-scale clinical trials in patients with colorectal cancer employing either in vivo activation or adoptive transfer of ex vivo expanded γδ T cells and suggest possible combinatorial approaches to treat colon cancer.

Multiple myeloma (MM) is a hematologic malignancy with a multistep evolutionary pattern, in which the pro-inflammatory and immunosuppressive microenvironment and genomic instability drive tumor evolution. MM microenvironment is rich in iron, released by pro-inflammatory cells from ferritin macromolecules, which contributes to ROS production and cellular damage. In this study, we showed that ferritin increases from indolent to active gammopathies and that patients with low serum ferritin had longer first line PFS (42.6 vs. 20.7 months and, p = 0.047, respectively) and OS (NR vs. 75.1 months and p = 0.029, respectively). Moreover, ferritin levels correlated with systemic inflammation markers and with the presence of a specific bone marrow cell microenvironment (including increased MM cell infiltration). Finally, we verified by bioinformatic approaches in large transcriptomic and single cell datasets that a gene expression signature associated with ferritin biosynthesis correlated with worse outcome, MM cell proliferation, and specific immune cell profiles. Overall, we provide evidence of the role of ferritin as a predictive/prognostic factor in MM, setting the stage for future translational studies investigating ferritin and iron chelation as new targets for improving MM patient outcome.

(1) Background: statins have been considered an attractive class of drugs in the pharmacological setting of COVID-19 due to their pleiotropic properties and their use correlates with decreased mortality in hospitalized COVID-19 patients. Furthermore, it is well known that statins, which block the mevalonate pathway, affect γδ T lymphocyte activation. As γδ T cells participate in the inflammatory process of COVID-19, we have investigated the therapeutical potential of statins as a tool to inhibit γδ T cell pro-inflammatory activities; (2) Methods: we harvested peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with mild clinical manifestations, COVID-19 recovered patients, and healthy controls. We performed ex vivo flow cytometry analysis to study γδ T cell frequency, phenotype, and exhaustion status. PBMCs were treated with Atorvastatin followed by non-specific and specific stimulation, to evaluate the expression of pro-inflammatory cytokines; (3) Results: COVID-19 patients had a lower frequency of circulating Vδ2+ T lymphocytes but showed a pronounced pro-inflammatory profile, which was inhibited by in vitro treatment with statins; (4) Conclusions: the in vitro capacity of statins to inhibit Vδ2+ T lymphocytes in COVID-19 patients highlights a new potential biological function of these drugs and supports their therapeutical use in these patients.

Background Autologous conditioned serum is a product of blood origin, with fragmented evidence of therapeutic properties in osteoarthritis chronic pain. This pilot observational prospective study aimed to evaluate the feasibility of a treatment with conditional autologous serum (ACS) in patients with severe chronic pain and grade I-III osteoarthritis and to describe its cytokine content. Methods We prospectively collected data on consecutive patients affected by osteoarthritis grade I to III and treated with four weekly injections of ACS at our outpatient pain service. The primary outcome was pain intensity, measured with the visual analogic scale (VAS). Additional outcomes were symptoms evaluated using joint district-specific scales. The study also evaluated concentrations of 48 cytokines and chemokines involved in the balance pro-inflammation/anti-inflammation and tissue repair in the ACS. Results We included 26 patients, mostly female (65.4%), with a median age of 63.5 years [IQR 58.25–73]. A median reduction of VAS of −3 cm [−5; −1.25] was observed 6 months after the first injection of ACS. The analysis showed a statistically significant difference between the values of VAS ( p < .01; X2 = 69.6; df = 6, N = 26) at the different time points. No adverse events were observed or reported by patients during the entire study period. Conclusions Conditional autologous serum may be a feasible option for patients with chronic pain due to grade I-III osteoarthritis refractory to other treatments. These preliminary findings should be confirmed in studies with adequate design.

Chronic inflammation is associated with the occurrence of several diseases. However, the side effects of anti-inflammatory drugs prompt the identification of new therapeutic strategies. Plant-derived extracellular vesicles (PDEVs) are gaining increasing interest in the scientific community for their biological properties. We isolated PDEVs from the juice of Citrus limon L. (LEVs) and characterized their flavonoid, limonoid and lipid contents through reversed-phase high-performance liquid chromatography coupled to electrospray ionization quadrupole time-of-flight mass spectrometry (RP-HPLC-ESI-Q-TOF-MS). To investigate whether LEVs have a protective role on the inflammatory process, murine and primary human macrophages were pre-treated with LEVs for 24 h and then were stimulated with lipopolysaccharide (LPS). We found that pre-treatment with LEVs decreased gene and protein expression of pro-inflammatory cytokines, such as IL-6, IL1-β and TNF-α, and reduced the nuclear translocation and phosphorylation of NF-κB in LPS-stimulated murine macrophages. The inhibition of NF-κB activation was associated with the reduction in ERK1-2 phosphorylation. Furthermore, the ability of LEVs to decrease pro-inflammatory cytokines and increase anti-inflammatory molecules was confirmed ex vivo in human primary T lymphocytes. In conclusion, we demonstrated that LEVs exert anti-inflammatory effects both in vitro and ex vivo by inhibiting the ERK1-2/NF-κB signalling pathway.

The metabolic changes that occur in tumor microenvironment (TME) can influence not only the biological activity of tumor cells, which become more aggressive and auto sustained, but also the immune response against tumor cells, either producing ineffective responses or polarizing the response toward protumor activity. γδ T cells are a subset of T cells characterized by a plasticity that confers them the ability to differentiate towards different cell subsets according to the microenvironment conditions. On this basis, we here review the more recent studies focused on altered tumor metabolism and γδ T cells, considering their already known antitumor role and the possibility of manipulating their effector functions by in vitro and in vivo approaches. γδ T cells, thanks to their unique features, are themselves a valid alternative to overcome the limits associated with the use of conventional T cells, such as major histocompatibility complex (MHC) restriction, costimulatory signal and specific tumor-associated antigen recognition. Lipids, amino acids, hypoxia, prostaglandins and other metabolic changes inside the tumor microenvironment could reduce the efficacy of this important immune population and polarize γδ T cells toward IL17 producing cells that play a pro tumoral role. A deeper knowledge of this phenomenon could be helpful to formulate new immunotherapeutic approaches that target tumor metabolisms.

We have read with great interest the paper by de Vries et al 1 reporting on the immune landscape of colorectal cancer (CRC) by high-dimensional mass cytometry, flow cytometry and single cell RNA sequencing. Among clusters of immune cells infiltrating CRC, authors have identified two populations of γδ T cells: one programmed cell death protein 1 (PD-1)+ population is almost exclusively found in DNA mismatch repair (MMR)-deficient (d) tumours, constitutes up to 8.4% of CD45+ cells and has an activated phenotype, and a PD-1− counterpart with a resting phenotype, which is also found in colorectal normal mucosa and MMR-proficient (p) tumours. Using deconvolution of transcriptomic datasets and single cell RNA sequencing, we have detected γδ cells in many different human tumours, including CRC,2 3 but it is important to know also their subset distribution, maturation states and functional profiles. In fact, there are two subsets of γδ T cells, those expressing Vδ1 which reside at mucosal sites and those expressing Vδ2 which are found in the blood but are recruited to the tumour site.4 Our previous study5 in tissue specimens of n=70 patients with CRC using flow cytometry has shown that γδ T cells account for around 4.5% of CD45+ cells both in normal and in CRC mucosa, and these data have been confirmed by data-mining of …

gamma delta T cells possess cytotoxic antitumor activity mediated by production of proinflammatory cytokines, direct cytotoxic activity, and regulation of the biological functions of other cell types. Hence, these features have prompted the development of therapeutic strategies in which gamma delta T cells agonists or ex vivo-expanded gamma delta T cells are administered to tumor patients. Several studies have shown that gamma delta T cells are an important component of tumor-infiltrating lymphocytes in patients affected by different types of cancer and a recent analysis of similar to 18,000 transcriptomes from 39 human tumors identified tumor-infiltrating.d T cells as the most significant favorable cancer-wide prognostic signature. However, the complex and intricate interactions between tumor cells, tumor microenvironment (TME), and tumor-infiltrating immune cells results in a balance between tumor-promoting and tumor-controlling effects, and gamma delta T cells functions are often diverted or impaired by immunosuppressive signals originating from the TME. This review focuses on the dangerous liason between gamma delta T cells and tumoral microenvironment and raises the possibility that strategies capable to reduce the immunosuppressive environment and increase the cytotoxic ability of gamma delta T cells may be the key factor to improve their utilization in tumor immunotherapy.