ABSTRACT
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.
Subject(s)
Risk-Taking , Sexual Behavior , Students, Medical , Humans , Male , Female , Students, Medical/statistics & numerical data , Students, Medical/psychology , Mexico/epidemiology , Adolescent , Adult , Young Adult , Sexual Behavior/statistics & numerical data , Prevalence , Cross-Sectional Studies , Surveys and Questionnaires , Sexually Transmitted Diseases/epidemiology , Unsafe Sex/statistics & numerical dataABSTRACT
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.
Subject(s)
Candida , Propolis , Antifungal Agents/pharmacology , Candida albicans , Humans , Mexico , Microbial Sensitivity Tests , Plant Extracts/chemistry , Propolis/chemistry , Propolis/pharmacologyABSTRACT
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.
Subject(s)
Papillomavirus Infections , Adult , Antibodies, Viral , DNA, Viral/analysis , Female , Humans , Immunoglobulin G , Mexico/epidemiology , Papillomaviridae , Prevalence , Risk Factors , Seroepidemiologic Studies , Students , Universities , Young AdultABSTRACT
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.
Subject(s)
Breast Neoplasms/pathology , CD8-Positive T-Lymphocytes/immunology , Lymphatic Metastasis/immunology , Neoplastic Stem Cells/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Aged , Aged, 80 and over , Breast/immunology , Breast/pathology , Breast Neoplasms/blood , Breast Neoplasms/diagnosis , Breast Neoplasms/immunology , CD4-CD8 Ratio , Dendritic Cells/immunology , Female , Humans , Lymph Nodes/immunology , Lymph Nodes/pathology , Lymphocytes, Tumor-Infiltrating , Middle Aged , Neoplasm Grading , Tumor Microenvironment/immunologyABSTRACT
Tumor expression of immune co-inhibitory ligands, such as PD-L1 and Galectin-9, have potential prognostic value in Hepatocellular Carcinoma (HCC). Circulating levels of these molecules, however, have hardly been studied. This study aims to assess the prognostic significance of circulating PD-L1 and circulating Galectin-9 in patients with resected HCC, and to compare their prognostic significance to the intra-tumoral expression of these same molecules. Archived tissues and stored peripheral blood samples from 81 patients who underwent HCC resection or liver transplantation, with curative intent, were used. Immunohistochemistry was performed to determine intra-tumoral expression of PD-L1 and Galectin-9, while ELISA was used to quantify their respective circulating levels. High circulating PD-L1 (HR 0.12, 95%CI 0.16-0.86, p = 0.011) and high circulating Galectin-9 (HR 0.11, 95%CI 0.15-0.85, p = 0.010) levels were both associated with improved HCC-specific survival. Surprisingly, there was no correlation between circulating levels of PD-L1 and Galectin-9 and their intra-tumoral expression levels. In fact, circulating levels of PD-L1 and Galectin-9 were predictive of HCC-specific survival independently of intra-tumoral levels and baseline clinicopathologic characteristics. Combined analysis of circulating levels and intra-tumoral expression of PD-L1 (HR 0.33, 95%CI 0.16-0.68, p = 0.002) and Galectin-9 (HR 0.27, 95%CI 0.13-0.57, p = 0.001) resulted in more confident prediction of survival. In conclusion, circulating PD-L1 and Galectin-9 levels prognostically differentiate resected HCC patients, independently of their intra-tumoral expression. Combining circulating and intra-tumoral expression levels of PD-L1 or Galectin-9 further improves the prognostic values of these immune biomarkers.
Subject(s)
B7-H1 Antigen/metabolism , Carcinoma, Hepatocellular/mortality , Galectins/metabolism , Liver Neoplasms/mortality , Adult , Aged , B7-H1 Antigen/blood , Biomarkers, Tumor/metabolism , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/surgery , Female , Galectins/blood , Hepatectomy , Humans , Liver/metabolism , Liver/surgery , Liver Neoplasms/blood , Liver Neoplasms/metabolism , Liver Neoplasms/surgery , Liver Transplantation , Male , Middle Aged , Prognosis , Survival Rate , Treatment Outcome , Young AdultABSTRACT
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.
Subject(s)
CD8-Positive T-Lymphocytes/immunology , Colorectal Neoplasms/immunology , Colorectal Neoplasms/secondary , Forkhead Transcription Factors/immunology , Liver Neoplasms/immunology , Lymphocytes, Tumor-Infiltrating/immunology , T-Lymphocytes, Regulatory/immunology , Adult , Aged , Aged, 80 and over , CD8-Positive T-Lymphocytes/pathology , Cohort Studies , Female , Humans , Immunohistochemistry , Liver Neoplasms/pathology , Male , Middle Aged , Prognosis , T-Lymphocyte Subsets/immunologyABSTRACT
BACKGROUND & AIMS: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Subject(s)
Antibodies, Monoclonal/pharmacology , Antibodies, Neutralizing/pharmacology , Antigens, CD , Antineoplastic Agents/pharmacology , Carcinoma, Hepatocellular/drug therapy , Hepatitis A Virus Cellular Receptor 2/antagonists & inhibitors , Immunotherapy/methods , Liver Neoplasms/drug therapy , Lymphocytes, Tumor-Infiltrating/drug effects , Programmed Cell Death 1 Receptor/antagonists & inhibitors , T-Lymphocytes/drug effects , Antigens, CD/immunology , Antigens, CD/metabolism , Antineoplastic Combined Chemotherapy Protocols/pharmacology , CTLA-4 Antigen/antagonists & inhibitors , CTLA-4 Antigen/immunology , CTLA-4 Antigen/metabolism , Carcinoma, Hepatocellular/immunology , Carcinoma, Hepatocellular/metabolism , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Cells, Cultured , Coculture Techniques , Cytokines/metabolism , Hepatitis A Virus Cellular Receptor 2/immunology , Hepatitis A Virus Cellular Receptor 2/metabolism , Humans , Liver Neoplasms/immunology , Liver Neoplasms/metabolism , Liver Neoplasms/pathology , Lymphocyte Activation/drug effects , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Programmed Cell Death 1 Receptor/immunology , Programmed Cell Death 1 Receptor/metabolism , Signal Transduction/drug effects , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Tumor Escape/drug effects , Tumor Microenvironment , Up-Regulation , Lymphocyte Activation Gene 3 ProteinABSTRACT
Even after the improvements made in recent years in early diagnosis and treatments, breast cancer is still the most common cancer and the leading cause of cancer death in women around the world. Several attempts to design new alternative therapies like immunotherapy have been evaluated in clinical trials, but they have shown limited efficacy. The failure of immunotherapy may be related to suppressive mechanisms in the tumor environment. Consequently, the development of new immunotherapy based treatment strategies is very important to understand the immunoregulatory mechanisms present in the tumor microenvironment. Some of the immunoregulatory mechanisms described in breast cancer will be discussed in this review.
Subject(s)
Breast Neoplasms/immunology , Breast Neoplasms/therapy , Immunotherapy , Antigen-Presenting Cells/immunology , Antigens, Neoplasm/immunology , Female , Humans , T-Lymphocytes/immunologyABSTRACT
In liver cancer tumor-infiltrating regulatory T cells (Ti-Treg) are potent suppressors of tumor-specific T-cell responses and express high levels of the Treg-associated molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and glucocorticoid-induced tumor necrosis factor receptor (GITR). In this study, we have evaluated the capacity of GITR-ligation, CTLA-4-blockade and a combination of both treatments to alleviate immunosuppression mediated by Ti-Treg. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC) or liver metastases from colorectal cancer (LM-CRC) we show that treatment with a soluble form of the natural ligand of GITR (GITRL), or with blocking antibodies to CTLA-4, reduces the suppression mediated by human liver tumor-infiltrating CD4+Foxp3+ Treg, thereby restoring proliferation and cytokine production by effector T cells. Importantly, combined treatment with low doses of both molecules exhibited stronger recovery of T cell function compared with either treatment alone. Our data suggest that in patients with primary and secondary liver cancer both GITR-ligation and anti-CTLA-4 mAb can improve the antitumor immunity by abrogating Ti-Treg mediated suppression.
ABSTRACT
CD4+ type 1 T regulatory (Tr1) cells have a crucial role in inducing tolerance. Immune regulation by these cells is mainly mediated through the secretion of high amounts of IL-10. Several studies have suggested that this regulatory population may be involved in tumor-mediated immune-suppression. However, direct evidence of a role for Tr1 cells in human solid tumors is lacking. Using ex vivo isolated cells from individuals with hepatocellular carcinoma (HCC; n = 39) or liver metastases from colorectal cancer (LM-CRC; n = 60) we identify a CD4+FoxP3-IL-13-IL-10+ T cell population in tumors of individuals with primary or secondary liver cancer that is characterized as Tr1 cells by the expression of CD49b and the lymphocyte activation gene 3 (LAG-3) and strong suppression activity of T cell responses in an IL-10 dependent manner. Importantly, the presence of tumor-infiltrating Tr1 cells is correlated with tumor infiltration of plasmacytoid dendritic cells (pDCs). pDCs exposed to tumor-derived factors enhance IL-10 production by Tr1 cells through up-regulation of the inducible co-stimulatory ligand (ICOS-L). These findings suggest a role for pDCs and ICOS-L in promoting intra-tumoral immunosuppression by Tr1 cells in human liver cancer, which may foster tumor progression and which might interfere with attempts of immunotherapeutic intervention.
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.
Subject(s)
Antibodies, Bacterial/immunology , Immunoglobulin G/immunology , Staphylococcal Infections/immunology , Staphylococcal Vaccines/immunology , Staphylococcus aureus/immunology , Tonsillitis/immunology , Adolescent , Adult , Female , Hot Temperature , Humans , Immunization , Male , Middle Aged , Recurrence , Staphylococcal Infections/microbiology , Staphylococcal Infections/prevention & control , Staphylococcal Vaccines/chemistry , Staphylococcus aureus/chemistry , Tonsillitis/microbiology , Tonsillitis/prevention & control , Young AdultABSTRACT
Remodeling of tumor microenvironment is a hallmark in the pathogenesis of liver cancer. Being a pivotal part of tumor stroma, multipotent mesenchymal stromal cells (MSCs), also known as mesenchymal stem cells (MSCs), are recruited and enriched in liver tumors. Owing to their tumor tropism, MSCs are now emerging as vehicles for anticancer drug/gene delivery against liver cancer. However, the exact impact of MSCs on liver cancer remains elusive, as a variety of effects of these cells that have been reported included a plethora of tumor-promoting effects and anti-oncogenic properties. This review aims to dissect the mechanistic insight regarding this observed discrepancy in different experimental settings of liver cancer. Furthermore, we call for caution using MSCs to treat liver cancer or even premalignant liver diseases, before conclusive evidence for safety and efficacy having been obtained.
Subject(s)
Liver Neoplasms/pathology , Mesenchymal Stem Cells/physiology , Cell Movement , Humans , Liver Neoplasms/therapy , Tumor MicroenvironmentABSTRACT
Our studies showed that tumor-infiltrating dendritic cells (DC) in breast cancer drive inflammatory Th2 (iTh2) cells and protumor inflammation. Here, we show that intratumoral delivery of the ß-glucan curdlan, a ligand of dectin-1, blocks the generation of iTh2 cells and prevents breast cancer progression in vivo. Curdlan reprograms tumor-infiltrating DCs via the ligation of dectin-1, enabling the DCs to become resistant to cancer-derived thymic stromal lymphopoietin (TSLP), to produce IL-12p70, and to favor the generation of Th1 cells. DCs activated via dectin-1, but not those activated with TLR-7/8 ligand or poly I:C, induce CD8+ T cells to express CD103 (αE integrin), a ligand for cancer cells, E-cadherin. Generation of these mucosal CD8+ T cells is regulated by DC-derived integrin αvß8 and TGF-ß activation in a dectin-1-dependent fashion. These CD103+ CD8+ mucosal T cells accumulate in the tumors, thereby increasing cancer necrosis and inhibiting cancer progression in vivo in a humanized mouse model of breast cancer. Importantly, CD103+ CD8+ mucosal T cells elicited by reprogrammed DCs can reject established cancer. Thus, reprogramming tumor-infiltrating DCs represents a new strategy for cancer rejection.
Subject(s)
Breast Neoplasms/immunology , Breast Neoplasms/pathology , CD8-Positive T-Lymphocytes/immunology , Dendritic Cells/immunology , Mucous Membrane/immunology , Animals , Breast Neoplasms/metabolism , CD8-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Cell Differentiation , Cell Line, Tumor , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Neoplastic/immunology , Dendritic Cells/cytology , Dendritic Cells/metabolism , Disease Models, Animal , Female , Humans , Lectins, C-Type/metabolism , Mice , Mucous Membrane/metabolism , Signal Transduction , T-Lymphocyte Subsets/drug effects , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Th2 Cells/drug effects , Th2 Cells/immunology , Transforming Growth Factor beta/metabolism , beta-Glucans/immunology , beta-Glucans/pharmacologyABSTRACT
Although the infiltration of mesenchymal stem (stromal) cells (MSCs) into different tumors is widely recognized in animal models, the question whether these MSCs have a positive or negative effect on disease progression remains unanswered. The aim of this study is to investigate whether human hepatocellular carcinoma (HCC) harbors MSCs and whether these MSCs affect tumor growth. We observed that cells capable of differentiation into both adipocyte and osteocyte lineages and expressing MSC markers can be cultured from surgically resected HCC tissues. In situ staining of human HCC tissues with a STRO-1 antibody showed that the tumor and tumor-stromal region are significantly enriched with candidate MSCs compared with adjacent tissue (n = 12, P < 0.01). In mice, coengraftment of a human HCC cell line (Huh7) with MSCs resulted in substantially larger tumors compared with paired engraftment of Huh7 alone (n = 8, P < 0.01). Consistently, coculturing Huh7 with irradiated MSCs significantly increased the number and the size of colonies formed. This enhancement of Huh7 colony formation was also observed by treatment of MSC-conditioned medium (MSC-CM), suggesting that secreted trophic factors contribute to the growth-promoting effects. Genome-wide gene expression array and pathway analysis confirmed the upregulation of cell growth and proliferation-related processes and downregulation of cell death-related pathways by treatment of MSC-CM in Huh7 cells. In conclusion, these results show that MSCs are enriched in human HCC tumor compartment and could exert trophic effects on tumor cells. Thus, targeting of HCC tumor MSCs may represent a new avenue for therapeutic intervention.
Subject(s)
Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/metabolism , Mesenchymal Stem Cells/metabolism , Animals , Antigens, Surface/metabolism , Carcinoma, Hepatocellular/pathology , Cell Culture Techniques , Cell Line, Tumor , Heterografts , Humans , Liver Neoplasms/pathology , Mesenchymal Stem Cells/cytology , Mice , Tumor Burden , Tumor Stem Cell AssayABSTRACT
Recently, we reported the accumulation of CD4+FOXP3+ regulatory T cells (Tregs) within the tumor mass of patients bearing liver cancer. Tumor-infiltrating Tregs (TiTregs) are active and potent suppressors of antitumor immunity. Importantly, treatment with GITRL reduced the immunosuppression mediated by TiTregs.
ABSTRACT
Alveolar macrophages (AM) and dendritic cells (DCs) are the main antigen presenting cells (APCs) in the respiratory tract. Whereas macrophages have been extensively studied in tuberculosis, in situ interactions of DC with Mycobacterium tuberculosis (Mtb) are poorly explored. We aimed to characterize lung APCs during pulmonary tuberculosis in Balb/C mice infected with Mtb H37Rv. Mtb-infection via the airways induced a delayed and continuous accumulation of DCs and AM in the lungs. While lung DCs increased after day 3 post-infection, macrophages increased after 2-3 weeks. Although both populations accumulated in lungs during the infection, DCs decreased in the late stages. Infection induced differential expression of co-stimulatory molecules in these lung APCs, decreasing to basal levels in both APCs in the late stages. A remarkable segregation was found regarding bacillary burden. Many macrophages contained numerous bacilli, but DC contained scarce mycobacteria or none. Mtb-infection also induced delayed accumulation of DC in draining lymph nodes. This delayed recruitment was not associated with a lack of IL-12p40, which was detected from day 3 post-infection. Although AM and lung DCs behave differently during pulmonary tuberculosis, Mtb apparently manipulates both lung APCs subverting early protective responses resulting in disease progression.
Subject(s)
Antigen-Presenting Cells/immunology , Dendritic Cells/immunology , Macrophages, Alveolar/immunology , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/immunology , Animals , Cell Movement , Cell Proliferation , Cells, Cultured , Disease Progression , Immunity, Cellular , Lung , Mice , Mice, Inbred BALB C , Mycobacterium tuberculosis/pathogenicity , VirulenceABSTRACT
UNLABELLED: 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.
Subject(s)
Carcinoma, Hepatocellular/immunology , Glucocorticoid-Induced TNFR-Related Protein/metabolism , Liver Neoplasms/immunology , T-Lymphocytes, Regulatory/physiology , Tumor Necrosis Factors/therapeutic use , Aged , Carcinoma, Hepatocellular/drug therapy , Cell Proliferation , Colorectal Neoplasms/pathology , Female , Humans , Immunotherapy , Inducible T-Cell Co-Stimulator Protein/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Lymphocyte Activation , Male , Middle AgedABSTRACT
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.
Subject(s)
Breast Neoplasms/physiopathology , Cytokines/physiology , Inflammation/physiopathology , Th2 Cells/physiology , Animals , Antibodies, Neoplasm/immunology , Dendritic Cells/immunology , Dendritic Cells/physiology , Female , Gene Expression Regulation, Neoplastic/physiology , Humans , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/physiology , Mice , Neoplasm Transplantation , OX40 Ligand/physiology , Th2 Cells/immunology , Thymic Stromal LymphopoietinABSTRACT
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.