Immunity results from a complex interplay between the antigen‐non‐specific innate immune system and the antigen‐specific adaptive immune system. The cells and molecules of the innate system employ ...non‐clonal recognition receptors including lectins, Toll‐like receptors, NOD‐like receptors, and helicases. B and T lymphocytes of the adaptive immune system employ clonal receptors recognizing antigens or their derived peptides in a highly specific manner. An essential link between innate and adaptive immunity is provided by dendritic cells (DCs). DCs can induce such contrasting states as immunity and tolerance. The recent years have brought a wealth of information on the biology of DCs revealing the complexity of this cell system. Indeed, DC plasticity and subsets are prominent determinants of the type and quality of elicited immune responses. In this article, we summarize our recent studies aimed at a better understanding of the DC system to unravel the pathophysiology of human diseases and design novel human vaccines.
Background and Objectives
Patients with isolated colorectal‐cancer‐liver‐metastases (CRCLM) frequently undergo metastatectomy. Tumor‐infiltrating‐lymphocytes (TILs) have prognostic potential in the ...setting of primary colorectal cancer, however, their role in CRCLM is less studied. We aimed to study the spatial distribution and prognostic role of tumor‐infiltrating CD8+ cytotoxic T‐cells and FoxP3+ regulatory T‐cells at the metastatic site of CRCLM patients.
Methods
TILs were isolated from fresh metastatic tissues of 47 patients with CRCLM. Archived paraffin‐embedded tissue, from the same patients, was retrieved. CD8+ and FoxP3+ cells, both in the intra‐tumoral and the peri‐tumoral compartments, were measured by immunohistochemistry on full tissue sections. Proportions of cytotoxic T‐cells (CD8+) and regulatory T‐cells (CD4+CD25+FoxP3+), within CD45+TILs, were measured by flow‐cytometry.
Results
By immunohistochemistry, individual densities of intra‐tumoral or peri‐tumoral CD8+ and FoxP3+ cells were not prognostic of survival. However, the intra‐tumoral, but not the peri‐tumoral, CD8+/FoxP3+ ratio was an independent predictor of survival (HR 0.43, 95%CI 0.19‐0.95, P = 0.032). By flow cytometry, the intra‐tumoral CD8+/regulatory T‐cell ratio was also an independent predictor of survival (HR 0.45, 95%CI 0.20‐0.99, P = 0.044).
Conclusions
The ratio of cytotoxic (CD8+) to regulatory (FoxP3+) T‐cells, in the intra‐tumoral compartment, but not in the peri‐tumoral compartment, can predict survival after resection of CRCLM.
The mechanisms that enable liver cancer to escape elimination by the immune system remain unclear, but their elucidation may provide novel therapeutic interventions. We investigated the influence of ...tumor‐infiltrating regulatory T cells on tumor‐specific T cell responses in patients with liver cancer, using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM‐CRC). Here we report that in both HCC and LM‐CRC, CD4+CD25+Foxp3+ regulatory T cells (Tregs) accumulate in the tumor milieu and are potent suppressors of autologous tumor‐specific T cell responses. Especially in LM‐CRC, where Treg accumulation is more prominent, there is good evidence for local proliferation of Tregs at the cancer site. We show that tumor Tregs up‐regulate the expression of glucocorticoid‐induced tumor necrosis factor receptor (GITR) compared with Tregs in tumor‐free liver tissue and blood. Importantly, treatment with soluble GITR ligand (GITRL) induces a decrease in the suppression mediated by the activated tumor‐infiltrating Tregs and restores the proliferative capacity and cytokine production of CD4+CD25− T cells. Conclusion: Our results show that tumor‐associated Tregs are critical for immune evasion in liver cancer, and we propose that GITRL constitutes a rational treatment for this disease. (HEPATOLOGY 2013)
Background
Tumor-infiltrating lymphocytes are an important component of the tumor microenvironment (TME) in breast cancer. They have been linked with tumor pathogenesis in advanced stages. However, ...little is known about their contribution in early phases. In this study, we analyzed the infiltration of leukocytes and cancer stem cells (CSC) in tumors from patients with early breast cancer.
Methods
Samples of blood and tumor tissue from 30 patients with breast cancer were collected, and the number of dendritic cells (DC), T cells, and CSC were analyzed by flow cytometry.
Results
Tumor-infiltrating CD4 and CD8 T cells expressed higher levels of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) compared with peripheral T cells. Regulatory T cells (Treg) were enriched in tumors and overexpressed glucocorticoid-induced TNFR-related protein and CTLA-4. Tumor Treg had a positive correlation with the amount of myeloid DC (mDC) and disease progression. The CD8/Treg ratio was associated with lymph node metastasis and tumor stages. The main subset of DC in early breast tumors was mDC, while plasmacytoid DC were almost absent. CSC were present in most tumors with higher frequencies in patients with lymph node metastasis. CSC were also associated with the amount of tumor-infiltrating Treg.
Conclusion
Early breast cancer has an inflammatory milieu characterized by mDC, Treg, and CSC infiltration. The frequencies of Treg, CSC and CD8/Treg ratio were associated with disease progression. The composition of leukocytes and the presence of CSC in early breast tumors should be considered for the development of new therapeutic approaches.
The human breast tumor microenvironment can display features of T helper type 2 (Th2) inflammation, and Th2 inflammation can promote tumor development. However, the molecular and cellular mechanisms ...contributing to Th2 inflammation in breast tumors remain unclear. Here, we show that human breast cancer cells produce thymic stromal lymphopoietin (TSLP). Breast tumor supernatants, in a TSLP-dependent manner, induce expression of OX40L on dendritic cells (DCs). OX40L(+) DCs are found in primary breast tumor infiltrates. OX40L(+) DCs drive development of inflammatory Th2 cells producing interleukin-13 and tumor necrosis factor in vitro. Antibodies neutralizing TSLP or OX40L inhibit breast tumor growth and interleukin-13 production in a xenograft model. Thus, breast cancer cell-derived TSLP contributes to the inflammatory Th2 microenvironment conducive to breast tumor development by inducing OX40L expression on DCs.
University students are at high risk of sexually transmitted infections due to the lack of adequate sexual education, as well as multiple associated factors, which lead to risky sexual practices. It ...is important to update data about sexual behaviors to identify the main factors associated with sexually risky behaviors. The present study aimed to evaluate the current prevalence of sexually risky practices in medical students. A cross-sectional study was conducted among medical students through an anonymous self-administered online questionnaire including demographic characteristics and sexual behaviors. We used descriptive statistics and multivariable regression to analyze the data collected. A total of 1520 undergraduate medical students aged between 18 and 28 years old were included in the study. Sixty percent of the students were sexually active with a higher proportion in men (70%), likewise, they had an earlier sexual debut (16.5 vs 16.9 years old), and a greater number of lifetime sexual partners than women (3.8 vs 2.2). The main sexual activity in both groups was vaginal sex with high use of condoms (75%), however, most of them (67%) reported having unprotected oral sex. Logistic regression analysis showed that condomless sex was associated with having oral sex, anal sex, and being female. The findings of this study showed that medical university students are involved in risky sexual behaviors, the major risk factor was unprotected oral sex. Based on these results, we recommended designing interventions to improve sexual education and preventive approaches from early stages such as in middle school students to mitigate sexually transmitted infections among medical university students.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
ABSTRACT
Currently Staphylococcus aureus is the predominant pathogen isolated from the respiratory tract of patients with recurrent tonsillitis. Because of an increase in multi‐drug resistant strains ...of S. aureus, there is a pressing need for effective treatments and preventive approaches to reduce the risk of invasive and life‐threatening infections. A preventive vaccine against S. aureus would have a tremendous clinical impact. However, multiple clinical trials have failed to identify an agent that can induce protective responses. Most trials have been based on subunit vaccines using one or a few purified antigens, which may not be enough to confer protection. Here, the impact of a whole‐cell vaccine comprised of heat‐inactivated S. aureus was investigated in patients with RT. The vaccine was well tolerated and had no significant local or systemic reactions. Immunization with heat‐inactivated S. aureus elicited a significant antibody response characterized by production of IgG1 and IgG2 antibodies and, to a lesser extent, of IgA antibodies. Notably, this response was associated with an important decrease in the incidence of tonsillitis and bacterial colonization of the oropharyngeal mucosa. Our results show that whole‐cell inactivated S. aureus is safe and capable of evoking specific antibody responses in patients with recurrent tonsillitis.
Ligand binding to inhibitory receptors on immune cells, such as programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA4), down-regulates the T-cell–mediated immune ...response (called immune checkpoints). Antibodies that block these receptors increase antitumor immunity in patients with melanoma, non–small-cell lung cancer, and renal cell cancer. Tumor-infiltrating CD4+ and CD8+ T cells in patients with hepatocellular carcinoma (HCC) have been found to be functionally compromised. We analyzed HCC samples from patients to determine if these inhibitory pathways prevent T-cell responses in HCCs and to find ways to restore their antitumor functions.
We collected HCC samples from 59 patients who underwent surgical resection from November 2013 through May 2017, along with tumor-free liver tissues (control tissues) and peripheral blood samples. We isolated tumor-infiltrating lymphocytes (TIL) and intra-hepatic lymphocytes. We used flow cytometry to quantify expression of the inhibitory receptors PD-1, hepatitis A virus cellular receptor 2 (TIM3), lymphocyte activating 3 (LAG3), and CTLA4 on CD8+ and CD4+ T cells from tumor, control tissue, and blood; we studied the effects of antibodies that block these pathways in T-cell activation assays.
Expression of PD-1, TIM3, LAG3, and CTLA4 was significantly higher on CD8+ and CD4+ T cells isolated from HCC tissue than control tissue or blood. Dendritic cells, monocytes, and B cells in HCC tumors expressed ligands for these receptors. Expression of PD-1, TIM3, and LAG3 was higher on tumor-associated antigen (TAA)-specific CD8+ TIL, compared with other CD8+ TIL. Compared with TIL that did not express these inhibitory receptors, CD8+ and CD4+ TIL that did express these receptors had higher levels of markers of activation, but similar or decreased levels of granzyme B and effector cytokines. Antibodies against CD274 (PD-ligand1 PD-L1), TIM3, or LAG3 increased proliferation of CD8+ and CD4+ TIL and cytokine production in response to stimulation with polyclonal antigens or TAA. Importantly, combining antibody against PD-L1 with antibodies against TIM3, LAG3, or CTLA4 further increased TIL functions.
The immune checkpoint inhibitory molecules PD-1, TIM3, and LAG3 are up-regulated on TAA-specific T cells isolated from human HCC tissues, compared with T cells from tumor-free liver tissues or blood. Antibodies against PD-L1, TIM3, or LAG3 restore responses of HCC-derived T cells to tumor antigens, and combinations of the antibodies have additive effects. Strategies to block PD-L1, TIM3, and LAG3 might be developed for treatment of primary liver cancer.
Human papillomavirus (HPV) is one of the most common causes of sexually transmitted diseases, and the main etiology of cervical cancer. This study was aimed to assess type-specific cervical HPV ...prevalence and their association with HPV-specific antibodies in a cohort of female university students. HPV genotyping was performed by amplifying and sequencing a fragment of the L1 protein. A BLAST search was performed to identify HPV types. HPV-specific IgG antibodies were measured by ELISA in serum samples. A total of 129 women participated, with an average age of 21.75 years. The prevalence of vaginal HPV infection was 74.42%. The most predominant high-risk HPV types were 18 (13.95%), 31 (10.85%), and 16 (9.3%). We found that early age at coitarche and a higher number of sexual partners were significantly associated with a high prevalence of HPV infection. In addition to sexual behavior, we observed that the presence of serum-specific IgG antibodies against HPV can impact the prevalence of the virus. Seropositivity to HPV-16 and HPV-18 was associated with a lower prevalence of HPV-16, but not for other HPV types. Of note, there was a lower proportion of HPV-specific seropositivity in women who had the presence of the same HPV type in a cervical specimen, suggesting an immunoregulatory mechanism associated with the viral infection. In conclusion, the prevalence of HPV in university women was higher than expected and it was associated with early age of sexual debut, an increasing number of sexual partners, and a low proportion of HPV seropositivity.
Infections caused by micro-organisms of the genus Candida are becoming a growing health problem worldwide. These fungi are opportunistic commensals that can produce infections—clinically known as ...candidiasis—in immunocompromised individuals. The indiscriminate use of different anti-fungal treatments has triggered the resistance of Candida species to currently used therapies. In this sense, propolis has been shown to have potent antimicrobial properties and thus can be used as an approach for the inhibition of Candida species. Therefore, this work aims to evaluate the anti-Candida effects of a propolis extract obtained from the north of Mexico on clinical isolates of Candida species. Candida species were specifically identified from oral lesions, and both the qualitative and quantitative anti-Candida effects of the Mexican propolis were evaluated, as well as its inhibitory effect on C. albicans isolate’s germ tube growth and chemical composition. Three Candida species were identified, and our results indicated that the inhibition halos of the propolis ranged from 7.6 to 21.43 mm, while that of the MFC and FC50 ranged from 0.312 to 1.25 and 0.014 to 0.244 mg/mL, respectively. Moreover, the propolis was found to inhibit germ tube formation (IC50 ranging from 0.030 to 1.291 mg/mL). Chemical composition analysis indicated the presence of flavonoids, including pinocembrin, baicalein, pinobanksin chalcone, rhamnetin, and biochanin A, in the Mexican propolis extract. In summary, our work shows that Mexican propolis presents significant anti-Candida effects related to its chemical composition, and also inhibits germ tube growth. Other Candida species virulence factors should be investigated in future research in order to determine the mechanisms associated with antifungal effects against them.
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