Fcγ receptors on aging neutrophilsObjective: Neutrophils are key effector cells of the innate immune system.They recognize antigens through membrane receptors, which are expressed during their maturation and activation. Neutrophils express FcγRII (CD32), FcγRIII (CD16), and FcγRI (CD64) after being activated by different factors such as cytokines and bacterial products. These receptors are involved with phagocytosis of IgG-opsonized microbes and enhance defense mechanisms.Based on that, our study seeks to compare the expression of FcγRII, FcγRIII, FcγRI, and CD11b on neutrophils from elderly and young subjects and their expression after in vitro activation with cytokines and LPS. Methodology: Neutrophils were isolated from human peripheral blood and from mice bone marrow by density gradient. After isolation, FCγRs expression was immediately analyzed by flow cytometry or after in vitro stimulation. Results:In freshly isolated cells, the percentage of FcγRIIIb + and CD11b + neutrophils were higher in samples from young individuals; FcγRIIIa expression was more prominent on aged neutrophils; FcγRIA expression was similar in all samples analyzed. Exposure to CXCL8 and LPS resulted in a higher percentage of FcγRIa + neutrophils on elderly individuals' samples but lower when compared with neutrophils from young donors. We observed that LPS caused an increase in FcγRIIa expression on aging human neutrophils. In contrast, FcγRIIIb expression in response to CXCL8 and LPS stimulation was not altered in the four groups. CD11b expression was lower in neutrophils from elderly individuals even in response to LPS and CXCL8. In mice, we observed differences only regarding CD11b expression, which was increased on aged neutrophils. LPS exposure caused an increase in all FcγRs. Conclusions:Our results suggest that, in humans, the overall pattern of FcγR expression and integrin CD11b are altered during aging and immunosenescence might contribute to age-related infection.

Squamous cell carcinoma (SCC) is the second most common form of skin cancer and the mechanism(s) involved in the progression of this tumor are unknown. Increases in the expression of IL-33/ST2 axis components have been demonstrated to contribute to neoplastic transformation in several tumor models and interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue. Based on these observations, we sought to determine the role of the IL-33/ST2 pathway during the development of SCC. Our findings show that ST2-deficiency led to a marked decrease in the severity of skin lesions, suggesting that ST2 signaling contributed to tumor development. An analysis of tumor lesions in wild-type and ST2KO mice revealed that a lack of ST2 was associated with specific and significant reductions in the numbers of CD4+ T cells, CD8+ T cells, dendritic cells, and macrophages. In addition, NK cells that were isolated from ST2KO mice exhibited higher cytotoxic activity than cells isolated from wild-type mice. Notably, ST2 deficiency resulted in lower IFN-γ, TNF-α, IL-10, and IL-17 production in tumor samples. Our findings indicate that the IL-33/ST2 pathway contributes to the development of SCC by affecting leukocyte migration to tumor microenvironment and impairing NK cytotoxic activity.

Androgen deprivation therapy (ADT) that antagonizes androgen receptor (AR) signaling has made significant increases to overall survival of prostate cancer patients. However, ADT is not curative, and patients eventually progress to castration resistant disease (CRPC). It has become evident that a subset of prostate cancers acquire ADT resistance through mechanisms independent of AR alteration or reprogramming of AR signaling. This approximately involves a quarter of prostate cancers progressing on ADT. Collectively, these tumors evolve via phenotypic plasticity and display the activation of developmental and stemness gene signatures as well as transitional programs including an epithelial-mesenchymal phenotype. Currently, no successful treatments exist for prostate cancer patients to inhibit or reverse prostate tumor progression that utilizes mechanisms of epi-plasticity. This overview will discuss epigenetic mechanisms that mediate phenotypic plasticity and the potential for targeting the epigenome to create a novel direction for combination strategies involving epigenetic therapy to provide durable response.

O carcinoma espinocelular (CEC) é a segunda forma de neoplasia cutânea mais prevalente. Os mecanismos exatos envolvidos na progressão desse tipo de tumor ainda não estão elucidados. Estudos recentes têm mostrado que a citocina IL33 é uma citocina reguladora da resposta imune adaptativa, principalmente como potente indutor do perfil Th2. Juntamente com seu receptor ST2, apresenta-se com os níveis elevados em alguns tipos de câncer, corroborando para a evidência de que essa citocina contribui para a carcinogênese. Baseado nessas informações, testamos a hipótese de que a presença de IL33 em carcinoma espinocelular, poderia estar relacionada a um melhor prognóstico. Neste estudo foram utilizadas amostras de carcinoma espinocelular, em diferentes gradações de malignidade tumoral (Grau I, Grau II e Grau III). Os resultados mostraram um infiltrado inflamatório mais intenso em tumores com Grau I e II. Imunorreatividade para IL33 foi observada em tumores de Grau I e II tanto por células epiteliais como por células do infiltrado inflamatório. A análise por microscopia confocal evidenciou que um grande número de células TCD4 + e TCD8 + que expressavam IL33 foi observado em tumores de Grau II. Esses resultados indicam a presença de um intenso infiltrado inflamatório e expressão de IL33 em amostras de carcinoma espinocelular com níveis menores de malignidade tumoral.