Immune system aging is becoming a field of increasing public health interest because of prolonged life expectancy, which is not paralleled by an increase in health expectancy. As age progresses, innate and adaptive immune systems undergo changes, which are defined, respectively, as inflammaging and immune senescence. A wealth of available data demonstrates that these two conditions are closely linked, leading to a greater vulnerability of elderly subjects to viral, bacterial, and opportunistic infections as well as lower post-vaccination protection. To face this novel scenario, an in-depth assessment of the immune players involved in this changing epidemiology is demanded regarding the individual and concerted involvement of immune cells and mediators within endogenous and exogenous factors and co-morbidities. This review provides an overall updated description of the changes affecting the aging immune system, which may be of help in understanding the underlying mechanisms associated with the main age-associated infectious diseases.

A previous report has shown that LGALS3BP (also known as 90K or Mac-2 BP) has antitumor activity in colorectal cancer (CRC) via suppression of Wnt signalling with a novel mechanism of ISGylation-dependent ubiquitination of β-catenin. The role of LGALS3BP in CRC prognosis was investigated. The role of LGALS3BP on CRC progression and clinical prognosis was analyzed by combining cell cultures, in vitro assays, and immunohistochemistry. Silencing of LGALS3BP in HCT-116 human colon cancer cells resulted in enhanced β-catenin expression that was reversed by addition of human recombinant LGALS3BP. Moreover, intra-tumor delivery of LGALS3BP reduced tumor growth of xenografts originating from LGALS3BP-silenced HCT-116 cells. Finally, in a series of 196 CRC patients, LGALS3BP expression in tumor tissue associated with clinical outcome. Patients with high LGALS3BP expression had lower risk of relapse and a longer overall survival time than those with low LGALS3BP expression. Multivariate analyses confirmed LGALS3BP expression status as the only independent prognostic factor of survival. These results provide evidence that low expression of LGALS3BP participates in malignant progression of CRC and implicates poor prognosis, highlighting its augmentation as a potential therapeutic approach.

Background: Assessment of T-cell diversity, besides giving insights about the molecular basis of tumor antigen recognition, has clinical implications since it provides criteria for evaluating antigen-specific T cells clinically relevant for spontaneous and vaccine-induced anti-tumor activity. Melan-A is one of the melanoma antigens most frequently recognized by peripheral and tumor-infiltrating lymphocytes in HLA-A2+ melanoma patients. Many clinical trials involving anti-tumor vaccination have been conducted using modified versions of this peptide.Methods: We conducted an in-depth characterization of 210 T-cell receptor beta chain (TRB) clonotypes derived from T cells of HLA-A2+ melanoma patients displaying cytotoxic activity against natural and A27L-modified Melan-A peptides. One hundred and thirteen Melan-A-specific clonotypes from melanoma-free subjects, 199 clonotypes from T-cell clones from melanoma patients specific for melanoma antigens other than Melan-A, and 305 clonotypes derived from T cells of HLA-A2+ individuals showing unrelated specificities, were used as control. After sequence analysis, performed according to the IMGT definitions, TRBV and TRBJ usage, CDR3 length and amino acid composition were compared in the four groups of clonotypes.Results: TRB sequences of Melan-A-specific clonotypes obtained from melanoma patients were highly heterogeneous, but displayed a preferential usage of few TRBV and TRBJ segments. Furthermore, they included a recurrent "public" amino acid motif (Glycine-Leucine-Glycine at positions 110-112-113 of the CDR3) rearranged with dominant TRBV and TRBJ segments and, in one case, associated with a full conservation of the entire TRB sequence.Conclusion: Contrary to what observed for public anti-Melan-A T-cell receptor alpha motifs, which had been identified in several clonotypes of both melanoma patients and healthy controls, the unexpectedly high contribution of a public TRB motif in the recognition of a dominant melanoma epitope in melanoma patients may provide important information about the biology of anti-tumor T-cell responses and improve monitoring strategies of anti-tumor vaccines.

Vav1 is one of the signalling proteins normally restricted to hematopoietic cells that results ectopically expressed in solid tumors, including breast cancer. By immunohistochemical analysis on TMAs containing invasive breast tumor from patients without lymph node involvement, we have found that Vav1 is expressed in almost all investigated cancers and shows a peculiar localization inside the nucleus of tumor cells. High amounts of nuclear Vav1 are positively correlated with low incidence of relapse, regardless phenotype and molecular subtype of breast neoplasia. In particular, Kaplan-Meier plots showed an elevated risk of distant metastasis in patients with low Vav1 expression compared with patients with high Vav1 expression in their tumors. Experiments performed with breast tumor-derived cells indicated that Vav1 negatively modulates their invasiveness in vitro and their metastatic efficiency in vivo, possibly by affecting the expression of genes involved in invasion and/or metastasis of breast tumors. Since the high heterogeneity of breast tumors makes difficult to predict the evolution of early breast neoplasias, the evaluation of nuclear Vav1 levels may help in the characterization and management of early breast cancer patients. In particular, Vav1 may serve as a prognostic biomarker and a target for new therapies aimed to prevent breast cancer progression.

Phospholipase Cγ1 (PLCγ1) is highly expressed in human tumours. Our previous studies reported that both stable and inducible PLCγ1 down-regulation can inhibit formation of breast-cancer-derived experimental lung metastasis. Further, high expression of PLCγ1 and its constitutively activated forms (i.e., PLCγ1-pY1253, PLCγ1-pY783) is associated with worse clinical outcome in terms of incidence of distant metastases, but not of local relapse in T1-T2, N0 breast cancer patients. In the present retrospective study, we analysed the prognostic role of PLCγ1 in early breast cancer patients stratified according to the St. Gallen criteria and to their menopausal status. PLCγ1-pY1253 and PLCγ1-pY783 protein expression levels were determined by immunohistochemistry on tissue microarrays, and were correlated with patients’ clinical data, using univariate and multivariate statistical analyses. In our series, the prognostic value of PLCγ1 overexpression was restricted to Luminal type tumours. From multivariate analyses, pY1253-PLCγ1High was an independent prognostic factor only in postmenopausal patients with Luminal-B tumours (hazard ratio [HR], 2.4; 95% confidence interval [CI], 1.1–5.3; P = 0.034). Conversely, PLCγ1-pY783High was a remarkably strong risk factor (HR, 20.1; 95% CI, 2.2–178.4; P = 0.003) for pre/perimenopausal patients with Luminal-A tumours. PLCγ1 overexpression is a strong predictive surrogate marker of development of metastases in early Luminal-A and -B breast cancer patients, being able to discriminate patients with high and low risk of metastases. Therefore, targeting the PLCγ1 pathway can be considered of potential benefit for prevention of metastatic disease.

Background: Benign prostatic hyperplasia (BPH) is the most common urologic disease among elderly men. The diagnosis of BPH is usually driven by lower urinary tract symptoms (LUTS) that can significantly affect patients’ quality of life. This phase II prospective, randomized double-blinded, placebo-controlled study aimed to determine the efficacy and safety of a novel whole tomato-based food supplement on LUTS of patients diagnosed with BPH. Methods: Forty consecutive patients with histologically proved BPH were randomized 1:1 to receive daily for 2 months a sachet (5 g) of a newly developed whole tomato food supplement (WTFS) (treatment = Group A) or placebo (Group B). Patients were asked to fill the International Prostatic Symptom Score (IPSS) questionnaire before and after treatment. Results: All but 1 patient in Group B successfully completed the scheduled regimen. No side effects were recorded. Unlike placebo, treatment significantly reduced (P < 0.0002) LUTS since mean IPSS decreased from 9.05 ± 1.15 to 7.15 ± 1.04 (paired t-test, two-tailed P-value < 0.001), and improved life quality (P < 0.0001). A trend toward a reduction of total PSA levels was observed in WTFS treated patients (8.98 ng/mL ± 1.52 vs 6.95 ± 0.76, P = 0.065), with changes being statistically significant only in the subgroup of patients with baseline levels above 10 ng/mL (18.5 ng/mL ± 2.7 vs 10.3 ± 2.1, P = 0.009). Conclusions: The new WTFS may represent a valid option for the treatment of symptomatic BPH patients. Unlike pharmacological treatments, the supplement is side effects free and highly accepted among patients.