Activation Of Host Immune System Research Articles

Metronomic chemotherapy in ovarian cancer

Translational research and the development of targeted therapies have transformed the therapeutic landscape in epithelial ovarian cancer over the last decade. However, recurrent ovarian cancer continues to pose formidable challenges to therapeutic interventions, necessitating innovative strategies to optimize treatment outcomes. Current research focuses on the development of pharmaceuticals that target potential resistance pathways to DNA repair pathways. However, the cost and toxicity of some of these therapies are prohibitive and majority of patients lack access to clinical trials. Metronomic chemotherapy, characterized by the continuous administration of low doses of chemotherapeutic agents without long treatment breaks, has emerged as a promising approach with potential implications beyond recurrent setting. It acts primarily by inhibition of angiogenesis and activation of host immune system. We here review the mechanism of action of metronomic chemotherapy, as well as its current role, limitations, and avenues for further research in the management of epithelial ovarian cancer.

Nanotechnology-Assisted Immunogenic Cell Death for Effective Cancer Immunotherapy.

Tumor vaccines have been used to treat cancer. How to efficiently induce tumor-associated antigens (TAAs) secretion with host immune system activation is a key issue in achieving high antitumor immunity. Immunogenic cell death (ICD) is a process in which tumor cells upon an external stimulus change from non-immunogenic to immunogenic, leading to enhanced antitumor immune responses. The immune properties of ICD are damage-associated molecular patterns and TAA secretion, which can further promote dendritic cell maturation and antigen presentation to T cells for adaptive immune response provocation. In this review, we mainly summarize the latest studies focusing on nanotechnology-mediated ICD for effective cancer immunotherapy as well as point out the challenges.

PTT/ PDT-induced microbial apoptosis and wound healing depend on immune activation and macrophage phenotype transformation

Antibiotics show unsuccessful application in biofilm destruction, which induce chronic infections and emergence of antibiotic resistant bacteria. Photodynamic therapy (PDT) and photothermal therapy (PTT), as widely accepted antimicrobial tools of phototherapy, could effectively activate the immune system and promote the proliferation of wound tissue, thus becoming the most promising therapeutic strategy to replace antibiotics and avoid drug-resistant strains. However, there is no consensus on whether antibacterial and wound healing achieved by PDT/PTT depend not only on the cytotoxic effect of the treatment itself, but also on the activation of host immune system. In this study, CaSiO3-ClO2@PDA-ICG nanoparticles (CCPI NPs) were designed as PDT/PTT antimicrobial model material. With the comparison of healing effect between wide-type mice and severely immunodeficient (C-NKG) mice, the dependence of PDT/PTT-induced microbial apoptosis and wound healing on immune activation and macrophage phenotype transformation was explored and verified. Furthermore, the induced phenotypic transformation of macrophages during PDT/PTT treatment was demonstrated to play crucial role in the improvement of epithelial-mesenchymal transformation (EMT). In summary, this study represents great significance for further identifying the role of immune system activation in antibacterial phototherapy and developing new treatment strategies for biofilm-infected wound healing. Statement of significanceA PDT/PTT combination therapy model nanoparticle was established for biofilm-infected wounds. Both microbial apoptosis and wound healing achieved by PDT/PTT combination therapy were highly dependent on the activated immune system, especially the M2 macrophage phenotype. PDT/PTT could promote the polarization of monocytes to the phenotype of M2 macrophages, which promotes EMT behavior of the tissue at the edge of the wound through the secretion of TGF-β1, thus accelerating wound healing.

The predictive value of high sensitivity troponin measurements in patients treated with immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer; however, at the potential cost of serious adverse events including cardiac injury. To assess the baseline and longitudinal changes in high sensitivity-Troponin (hs-Tn) in patients treated with pembrolizumab as a potential predictor for the development of major adverse cardiac events (MACE) and survival. We performed a retrospective analysis of cancer patients treated with pembrolizumab at our center. All participants had baseline measurements of hs-TnI prior to initiation of pembrolizumab (T1), with half of the patients performing follow-up measurements at their second encounter for therapy introduction (T2). We first evaluated the prevalence of abnormally elevated serum hs-TnI (> 50nanogram per liter) at T1 and T2. We then evaluated the predictive value of abnormal levels at T1 or T2 in relation to the development of MACE (composite outcomes of myocarditis, acute coronary syndrome, heart failure, venous thromboembolism, cardiovascular hospitalization and cardiovascular mortality) and all-cause mortality. Among 135 patients, the mean age was 72years, predominantly male (61%). Abnormally elevated hs-TnI at T1 was observed in 7 (5%) patients and emerged as a significant independent predictor for MACE (HR 8.1, 95% CI 1.67-37.4, p = 0.009) and all-cause mortality (HR 5.37, 95% CI 2.1-13.57, p < 0.001). Abnormally elevated hs-TnI at T2 was observed in 8 (11%) patients and emerged as a significant independent predictor for MACE (HR 10.49, 95% CI 1.68-65.5, p = 0.009), but not for mortality (p = 0.200). Abnormally elevated baseline and follow-up hs-TnI served as significant independent predictors for MACE, with an increased risk of development being 8-tenfold. Furthermore, elevated baseline hs-TnI showed a predictive value for all-cause mortality. Central illustration: Novel immune checkpoint inhibitor (ICIs) therapy has been found to revolutionize cancer therapy through increased activation of host immune systems to target and reduce tumor burden, but may come at the cost of serious adverse cardiac events. Identification of early biomarkers for the prediction and detection of these events is necessary.

A Chimera of Th1 Stimulatory Proteins of Leishmania donovani Offers Moderate Immunotherapeutic Efficacy with a Th1-Inclined Immune Response against Visceral Leishmaniasis.

Immunotherapy, a treatment based on host immune system activation, has been shown to provide a substitute for marginally effective conventional chemotherapy in controlling visceral leishmaniasis (VL), the deadliest form of leishmaniasis. As the majority of endemic inhabitants exhibit either subclinical or asymptomatic infection which often develops into the active disease state, therapeutic intervention seems to be an important avenue for combating infections by stimulating the natural defense system of infected individuals. With this perspective, the present study focuses on two immunodominant Leishmania (L.) donovani antigens (triosephosphate isomerase and enolase) previously proved to be potent prophylactic VL vaccine candidates, for generating a recombinant chimeric antigen. This is based on the premise that in a heterogeneous population, a multivalent antigen vaccine would be required for an effective response against leishmaniasis (a complex parasitic disease). The resulting molecule rLdT-E chimeric protein was evaluated for its immunogenicity and immunotherapeutic efficacy. A Th1 stimulating adjuvant BCG was employed with the protein which showed a remarkable 70% inhibition of splenic parasitic multiplication positively correlated with boosted Th1 dominant immune response against lethal L. donovani challenge in hamsters as evidenced by high IFN-γ and TNF-α and low IL-10. In addition, immunological analysis of antibody subclass presented IgG2-based humoral response besides considerable delayed-type hypersensitivity and lymphocyte proliferative responses in rLdT-E/BCG-treated animals. Our observations indicate the potential of the chimera towards its candidature for an effective vaccine against Leishmania donovani infection.

Systemic inflammation and protease profile of Afro-Caribbean patients with sepsis.

Objectives:Sepsis is one of the leading causes of morbidity and mortality within the healthcare system and remains a diagnostic and therapeutic challenge. A major issue in the diagnosis of sepsis is understanding the pathophysiologic mechanism, which revolves around host immune system activation and dysregulated responses. African Americans are more likely to experience severe sepsis with higher mortality rates compared to the general population. This pilot study characterized multiple inflammatory markers and proteases in plasma of primarily African American and Afro-Caribbean patients with mild sepsis.Methods:Plasma was collected from 16 healthy controls and 15 subjects presenting with sepsis, on admission, and again upon resolution of the signs of sepsis, defined as a resolution of sepsis criteria. Plasma samples were analyzed for cytokines, chemokines, and proteases using multiplex bead assays.Results:Elevated levels of granulocyte colony-stimulating factor, interleukin-10, interleukin-15, interleukin-1 receptor antagonist, interleukin-8, interferon gamma-induced protein 10, monocyte chemoattractant protein-1, matrix metallopeptidase 12, and cathepsin S were identified in plasma from sepsis patients on admission compared to control subjects. Interleukin-6, interleukin-8, granulocyte colony-stimulating factor, and cathepsin S were reduced in sepsis patients upon clinical resolution of sepsis.Conclusion:These findings profile the circulating inflammatory cytokines, chemokines, and proteases in African Americans and Afro-Caribbean patients during sepsis. The role of these targets in sepsis needs addressing in this patient population.

Nanoparticle mediated cancer immunotherapy.

The versatility and nanoscale size have helped nanoparticles (NPs) improve the efficacy of conventional cancer immunotherapy and opened up exciting approaches to combat cancer. This review first outlines the tumor immune evasion and the defensive tumor microenvironment (TME) that hinders the activity of host immune system against tumor. Then, a detailed description on how the NP based strategies have helped improve the efficacy of conventional cancer vaccines and overcome the obstacles led by TME. Sustained and controlled drug delivery, enhanced cross presentation by immune cells, co-encapsulation of adjuvants, inhibition of immune checkpoints and intrinsic adjuvant like properties have aided NPs to improve the therapeutic efficacy of cancer vaccines. Also, NPs have been efficient modulators of TME. In this context, NPs facilitate better penetration of the chemotherapeutic drug by dissolution of the inhibitory meshwork formed by tumor associated cells, blood vessels, soluble mediators and extra cellular matrix in TME. NPs achieve this by suppression, modulation, or reprogramming of the immune cells and other mediators localised in TME. This review further summarizes the applications of NPs used to enhance the efficacy of cancer vaccines and modulate the TME to improve cancer immunotherapy. Finally, the hurdles faced in commercialization and translation to clinic have been discussed and intriguingly, NPs owe great potential to emerge as clinical formulations for cancer immunotherapy in near future.

Commensal bacteria prevent pathogenic bacterial infection by inducing of activation of host immune system

Countless numbers of bacteria inhabit the intestinal tract. One of the important functions of gut microbiota is the "colonization resistance" against infection by pathogenic microorganisms. However, detailed mechanism of the colonization resistance of intestinal bacteria is still largely unknown. We tried to identify molecular and cellular mechanism of it and found that antigen presentation by dendritic cells is required for the induction of intestinal segmented filamentous bacteria (SFB)-induced T helper 17 (Th17) cells that contribute to the protection against infection by Citrobacter rodentium. We further identified that gut Th17 cells selectively recognize antigens derived from SFB. We also revealed that SFB induce α1,2-fucose, one of carbohydrate chains, expressed on the intestinal epithelial cells mediated by group 3 innate lymphoid cells. Epithelial α1,2-fucose protected against infection by pathogenic bacterium Salmonella typhimurium. Furthermore, it was found that intestinal bacteria inhibit colonization of the pathogenic fungus Candida albicans as well as pathogenic bacteria. From these studies, detailed mechanism of "colonization resistance" against pathogenic microorganisms by intestinal bacteria has been clarified.

The effects of glyphosate and AMPA on the mediterranean mussel Mytilus galloprovincialis and its microbiota

Glyphosate, the most widely used herbicide worldwide, targets the 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) enzyme in the shikimate pathway found in plants and some microorganisms. While the potential for glyphosate to induce a broad range of biological effects in exposed organisms has been demonstrated, the global molecular mechanisms of toxicity and potential effects in bacterial symbionts remain unclear, in particular for ecologically important marine species such as bivalve molluscs. Here, the effects of glyphosate (GLY), its degradation product aminomethylphosphonic acid (AMPA), and a mixture of both (MIX) on the mussel M. galloprovincialis were assessed in a controlled experiment. For the first time, next generation sequencing (RNA-seq and 16S rRNA amplicon sequencing) was used to evaluate such effects at the molecular level in both the host and its respective microbiota. The results suggest that the variable capacity of bacterial species to proliferate in the presence of these compounds and the impairment of host physiological homeostasis due to AMPA and GLY toxicity may cause significant perturbations to the digestive gland microbiota, as well as elicit the spread of potential opportunistic pathogens such as Vibrio spp.. The consequent host-immune system activation identified at the molecular and cellular level could be aimed at controlling changes occurring in the composition of symbiotic microbial communities. Overall, our data raise further concerns about the potential adverse effects of glyphosate and AMPA in marine species, suggesting that both the effects of direct toxicity and the ensuing changes occurring in the host-microbial community must be taken into consideration to determine the overall ecotoxicological hazard of these compounds.

Elevated Cytotoxic T Cells is Associated with Allosensitization of Patients Supported by a Continuous-Flow Left Ventricular Assist Device

Introduction Use of CFLVADs as a BTT continues to increase. The mechanisms of host immune system activation following implantation leading to allosensitization complicating transplantation outcomes are not well understood. Hypothesis We hypothesize that pre-implant cell profiles may predict post-implant allosensitization. Methods Plasma and PBMC samples were collected before implant (D0), 48 hours post-implant (D2) and 8 days post-implant (D8) in 12 CFLVAD patients. HLA class I and II antibody profiles were obtained pre and post-implant. Calculated panel of reactive antibodies (cPRA) were calculated using the OPTN calculator. Plasma aliquots were randomized and performed in duplicate. Lymphocyte phenotypes were analyzed by multiparameter flow cytometry across 3 randomized panels. Results Mean age of patients was 53.6±15.3 years, 50% were female and 33% had ischemic cardiomyopathy. Following implant there was a significant increase of Treg cells (CD4+Foxp3+CD25+ 1.07±0.39 p=0.005), T effector cells (CD4+Foxp3−CD25+ 13.2±2.83 p=0.0007) and B cells (CD3−CD19+ 7.17±2.93 p=0.032). This was accompanied with a decrease in CD3+ T cells (-10.1±3.69 p=0.019), cytotoxic T cells (CD3+CD8+ -3.28±1.12 p=0.014), and NK cells (CD3−CD19−CD56+ -3.86±1.72 p=0.047). Three patients had an increase in cPRA post-implant. All 3 patients had significantly increased cytotoxic T cells compared to patients with no increase (D0 18.4±2.46 vs 7.69±5.79 p=0.013); (D2 15.8±3.12 vs 6.74±3.61 p=0.012); (D8 13.9±3.64 vs 4.83±2.99 p=0.002) ( Figure 1 ). A significant increase in the plasma cytokines IL-6 (D0 79.7 D2 1320 D8 240 p Conclusion We show an impaired cellular immunity characterized by an acute rise in Treg, T-effector cells as well as B cells while the tissue aggressive response decreased. IL-6, IL-8 and G-CSF increased significantly post-implant in sensitized patients. Surprisingly, high CD8+ T cells pre-implant were associated with an increased cPRA in our cohort. CD8+ T cells in these patients decreased after implant but remained 2-fold higher than those patients with no increase in cPRA. Higher levels of cytotoxic T cells pre-implant may predict post CFLVAD implant allosensitization. Characterizing pre-implant cell profiles may be useful in identifying appropriate CFLVAD recipients.

Presence of Pig IgG and IgM in Sera Samples From Baboons After an Orthotopic Liver Xenotransplantation

IntroductionThe immunorejection in xenotransplantation has mostly been studied from the host's immune system activation point of view and there is very little information about the graft-vs-host reaction. ObjectivesTo validate an enzyme-linked immunosorbent assay (ELISA) test for porcine IgM and IgG quantitation, the assessment of porcine IgG and IgM in sera samples from baboons after liver orthotopic xenotransplantation or in human plasma after xenotransfusion through pig organs, and to assess the presence of porcine immunoglobulin in a baboon after plasmapheresis to a complete change of plasma after 4 passages through pig liver. Materials and MethodsTwo commercial ELISA kits for pig IgG and IgM quantitation were evaluated for cross reactivity with samples from baboons, Rhesus monkeys, squirrel monkeys, and humans. Then, samples from 18 baboons after orthotopic liver xenotransplantation were studied for porcine IgG and IgM. To understand the phenomenon, human plasma samples after xenotransfusion 1, 2, 3, or 4 times through liver or kidney were assessed for porcine IgG presence and finally, the porcine IgG were quantified in sera samples obtained during more than 4 years from a baboon after plasmapheresis with baboon plasma after xenotransfusion 4 times through a pig liver. ResultsPorcine IgG and IgM were found in samples from xenotransplanted baboon during all survival. The quantity of porcine IgG in plasma after xenotransfusion correlated with the number of passages through the pig liver, and the IgG were completely cleared from the baboon 16 days after plasmapheresis and complete substitution of plasma after 4 xenotransfusions through a pig liver.

Metabolomics of Therapy Response in Preclinical Glioblastoma: A Multi-Slice MRSI-Based Volumetric Analysis for Noninvasive Assessment of Temozolomide Treatment.

Glioblastoma (GBM) is the most common aggressive primary brain tumor in adults, with a short survival time even after aggressive therapy. Non-invasive surrogate biomarkers of therapy response may be relevant for improving patient survival. Previous work produced such biomarkers in preclinical GBM using semi-supervised source extraction and single-slice Magnetic Resonance Spectroscopic Imaging (MRSI). Nevertheless, GBMs are heterogeneous and single-slice studies could prevent obtaining relevant information. The purpose of this work was to evaluate whether a multi-slice MRSI approach, acquiring consecutive grids across the tumor, is feasible for preclinical models and may produce additional insight into therapy response. Nosological images were analyzed pixel-by-pixel and a relative responding volume, the Tumor Responding Index (TRI), was defined to quantify response. Heterogeneous response levels were observed and treated animals were ascribed to three arbitrary predefined groups: high response (HR, n = 2), TRI = 68.2 ± 2.8%, intermediate response (IR, n = 6), TRI = 41.1 ± 4.2% and low response (LR, n = 2), TRI = 13.4 ± 14.3%, producing therapy response categorization which had not been fully registered in single-slice studies. Results agreed with the multi-slice approach being feasible and producing an inverse correlation between TRI and Ki67 immunostaining. Additionally, ca. 7-day oscillations of TRI were observed, suggesting that host immune system activation in response to treatment could contribute to the responding patterns detected.

Inhibition of gold nanoparticles (AuNPs) on pathogenic biofilm formation and invasion to host cells.

Owing to the growing infectious diseases caused by eukaryotic and prokaryotic pathogens, it is urgent to develop novel antimicrobial agents against clinical pathogenic infections. Biofilm formation and invasion into the host cells are vital processes during pathogenic colonization and infection. In this study, we tested the inhibitory effect of Au nanoparticles (AuNPs) on pathogenic growth, biofilm formation and invasion. Interestingly, although the synthesized AuNPs had no significant toxicity to the tested pathogens, Candida albicans and Pseudomonas aeruginosa, the nanoparticles strongly inhibited pathogenic biofilm formation and invasion to dental pulp stem cells (DPSCs). Further investigations revealed that AuNPs abundantly bound to the pathogen cells, which likely contributed to their inhibitory effect on biofilm formation and invasion. Moreover, treatment of AuNPs led to activation of immune response-related genes in DPSCs, which may enhance the activity of host immune system against the pathogens. Zeta potential analysis and polyethylene glycol (PEG)/polyethyleneimine (PEI) coating tests further showed that the interaction between pathogen cells and AuNPs is associated with electrostatic attractions. Our findings shed novel light on the application of nanomaterials in fighting against clinical pathogens, and imply that the traditional growth inhibition test is not the only way to evaluate the drug effect during the screening of antimicrobial agents.

Augmenting Neutrophil Function By Administration of Peg-Filgrastim Potentiates Rituximab and Is Safe in Patients with Indolent B-Cell Non-Hodgkin Lymphomas: Results of a Phase II Study

Background: Pre-clinical studies have shown that host immune system activation by G-CSF/GM-CSF enhances the biologic activity of rituximab through up-regulation of CD11b/18 expression on neutrophils, increase in the number of circulating granulocytes and higher CD20 epitope density on tumor cells. To further explore the role of augmenting neutrophil function in B-cell lymphoma, we conducted an open-label, single-arm, phase II study evaluating the safety and clinical efficacy of peg-filgrastim and rituximab in patients with low-grade CD20 positive B-cell Non-Hodgkin lymphomas (B-NHL) [chronic lymphocytic leukemia (CLL), follicular lymphoma (FL) and marginal zone lymphoma (MZL)]. (NCT01682044)Materials and methods: Twenty patients with untreated or relapsed/refractory indolent lymphoma were treated with rituximab (375 mg/m2) every other week for 4 doses, and after 8 weeks every 2 months for 4 additional doses (total 8 doses). Peg-filgrastim (6mg) was administered subcutaneously 3 days before each dose of rituximab. Clinical responses and tolerability were examined according to standard international criteria. Biologic monitoring included evaluation of phenotype characteristics of host neutrophils, changes in oxidative burst, and in vitro functional assays including CMC and ADCC at baseline and before each dose of rituximab.Results: Baseline patient characteristics were as follows: Median age: 64 (28-86) yrs; 70% male; FL: 70%, CLL: 20%, MZL: 10%; Ann-Arbor stage- II- 10%, III- 30% and IV- 60%; disease status- newly diagnosed: 1, rituximab refractory: 2, relapsed ≥1 line of therapies: 17. Median number of prior therapies was 2 (1-5); 75% had previously received rituximab and 90% had received prior anti-CD20 monoclonal antibody therapy. The addition of peg-filgrastim to rituximab was well tolerated, and did not increase the frequency or severity of rituximab-related toxicities. Most of the adverse events were grade 1-2 infusion-related toxicities. One patient developed grade 4 hyperuricemia. One patient with MZL died while on treatment due to disease progression. The overall response rate (ORR) was 60% (12/20) with a complete response (CR) rate of 35% (7/20). Median progression-free survival (PFS) was 17.9 months (95% CI- 9.9-27.6 months); median overall survival (OS) was not reached. A shorter time-to-peak oxidative burst after first dose of peg-filgrastim was associated with higher rates of CR (p= 0.04) and longer PFS (p=0.03, figure 1). Though intensity of peak oxidative burst did not correlate statistically with outcomes, patients who achieved CR (and OR) had consistently higher free radical levels compared to those who did not, especially during the first 2 months of treatment. This trend waned during the latter part of therapy suggesting neutrophil exhaustion. Further analyses are ongoing to evaluate the association between rituximab ex vivo immunological assays and clinical endpoints outcomes.Conclusion: The combination of peg-filgrastim and rituximab was well tolerated with favorable response rates and PFS compared to historical controls treated with single-agent rituximab. Augmented neutrophil function was associated with higher CR rates and OS. Our results support further evaluation of strategies that enhance the innate immune system to improve rituximab activity in B-cell lymphoma. [Display omitted] DisclosuresOff Label Use: Pegfilgrastim has been combined with rituximab in this phase 2 study for treatment of indolent B-cell Non-Hodgkin lymphoma.. Czuczman:Celgene: Employment; Immunogen: Other: Advisory board; MorphoSys: Consultancy; Boehringer-Ingelheim: Other: Advisory Board.

The thyroid adverse effects of novel anti-neoplastic agents

Novel anti-neoplastic agents, including targeted therapies and immunotherapies, show promising results in managing both solid and hematological malignancies: their mechanisms of action include direct effect on signaling of tumor cells, anti-angiogenetic effects and host's immune system activation leading to enhanced anti-tumor response. However new typical side effects have emerged including thyroid dysfunction, which can manifest as development of thyroid auto-immunity, primary hypothyroidism, and thyrotoxicosis. Immune checkpoint inhibitors (monoclonal antibodies targeting different ligands on T-cells and tumor cells), have shown striking results in improving prognosis of patients with metastatic melanoma and are now under investigation for several malignancies. These drugs lead to T-cell reactivation against tumor cells and host cells, causing both anti-neoplastic response and autoimmune adverse events. Autoimmune thyroid disease includes primary hypothyroidism, thyrotoxicosis and euthyroid Graves’ ophtalmopathy. In this setting, hypothyroidism may be a consequence of autoimmune hypophysitis as well. Tyrosine-kinase inhibitors, currently used for gastrointestinal stromal tumors, renal carcinoma and other malignancies, frequently lead to thyroid dysfunction and many mechanisms have been advocated, including capillary regression within the thyroid gland, direct toxic effects on thyrocytes and peripheral effects on thyroid hormone metabolism. Other immunotherapies, such as denileukin diftitox, alemtuzumab and lenalidomide can cause thyroid adverse effect as well. Thyroid dysfunction can be associated with non specific signs and symptoms which can overlap with the effects of either anti-cancer therapies or the underlying disease. Therefore clinicians should be aware of thyroid adverse effects of novel anti-neoplastic agents, in order not to overlook a condition that potentially affects patients’ morbidity and mortality.

Innovative Tratments of Non Muscle Invasive Bladder Cancer

Bladder cancer represents the second most common neoplasm of the urinary tract and the fourth in general among all the neoplastic pathologies for the male gender; in females, it is the eighth most frequent among all cancers. At the initial diagnosis, 70% of bladder tumors are non-muscle invasive. Treatment of this stage is multimodal, both surgical and pharmacological; the aim is not only to remove the tumor completely but also to prevent tumor recurrence and to inhibit its progression. The treatment for non-muscle invasive bladder cancer is a current topic in the scientific community and it is represented by the endoscopic resection of the tumor, which is generally followed by the adjuvant intravesical treatment with chemotherapy or immunotherapy agents, according to the different risk groups. Benefits and limits of intravesical therapies have been known for long; the aim of this study is to present new drugs or new treatment patterns which could emerge as a valid therapeutic alternative to conventional treatments, given the fact that, regardless of the type of treatment, 2/3 of the patients with a diagnosis of non-muscle invasive bladder cancer have a disease recurrence, and the 10-20% of these show a progression to a muscle-invasive tumor. Furthermore, the failure of intravesical therapy implies another therapeutic option, such as radical cystectomy for non-muscle invasive bladder cancer. According to this fact, new strategies include the activation of host immune system and the optimization of cytotoxic effects of chemotherapeutic drugs. Although most of these studies are still in a pre-clinical phase, the experimental outcomes and the initial results in humans are encouraging.

In the field: exploiting the untapped potential of immunogenic modulation by radiation in combination with immunotherapy for the treatment of cancer.

Radiation has long been the standard of care for many types of cancer. It is employed to locally eradicate tumor cells as well as alter tumor stroma with either curative or palliative intent. Radiation-induced cell damage is an immunologically active process in which danger signals are released that stimulate immune cells to phagocytose and present locally released tumor-associated antigens (TAAs). Recent studies have indicated that radiotherapy can also alter the phenotype of cancer cells that remain after treatment. These cells upregulate TAAs as well as markers, including major histocompatibility complex and costimulatory molecules, that make them much more immunostimulatory. As our understanding of the immunomodulatory effects of radiation has improved, interest in combining this type of therapy with immune-based therapies for the treatment of cancer has grown. Therapeutic cancer vaccines have been shown to initiate the dynamic process of host immune system activation, culminating in the recognition of host cancer cells as foreign. The environment created after radiotherapy can be exploited by active therapeutic cancer vaccines in order to achieve further, more robust immune system activation. This review highlights preclinical studies that have examined the alteration of the tumor microenvironment with regard to immunostimulatory molecules following different types of radiotherapy, including external beam radiation, radiolabeled monoclonal antibodies, bone-seeking radionuclides, and brachytherapy. We also emphasize how combination therapy with a cancer vaccine can exploit these changes to achieve improved therapeutic benefit. Lastly, we describe how these laboratory findings are translating into clinical benefit for patients undergoing combined radiotherapy and cancer vaccination.

The Capsule of Porphyromonas gingivalis Leads to a Reduction in the Host Inflammatory Response, Evasion of Phagocytosis, and Increase in Virulence

Periodontal disease is a chronic oral inflammatory disease that is triggered by bacteria such as Porphyromonas gingivalis. P. gingivalis strains exhibit great heterogeneity, with some strains being encapsulated while others are nonencapsulated. Although the encapsulated strains have been shown to be more virulent in a mouse abscess model, so far the role of the capsule in P. gingivalis interactions with host cells is not well understood and its role in virulence has not been defined. Here, we investigated the contribution of the capsule to triggering a host response following microbial infection, as well as its protective role following bacterial internalization by host phagocytic cells with subsequent killing, using the encapsulated P. gingivalis strain W50 and its isogenic nonencapsulated mutant, PgC. Our study shows significant time-dependent upregulation of the expression of various groups of genes in macrophages challenged with both the encapsulated and nonencapsulated P. gingivalis strains. However, cells infected with the nonencapsulated strain showed significantly higher upregulation of 9 and 29 genes at 1 h and 8 h postinfection, respectively, than cells infected with the encapsulated strain. Among the genes highly upregulated by the nonencapsulated PgC strain were ones coding for cytokines and chemokines. Maturation markers were induced at a 2-fold higher rate in dendritic cells challenged with the nonencapsulated strain for 4 h than in dendritic cells challenged with the encapsulated strain. The rates of phagocytosis of the nonencapsulated P. gingivalis strain by both macrophages and dendritic cells were 4.5-fold and 7-fold higher, respectively, than the rates of phagocytosis of the encapsulated strain. On the contrary, the survival of the nonencapsulated P. gingivalis strain was drastically reduced compared to the survival of the encapsulated strain. Finally, the encapsulated strain exhibited greater virulence in a mouse abscess model. Our results indicate that the P. gingivalis capsule plays an important role in aiding evasion of host immune system activation, promoting survival of the bacterium within host cells, and increasing virulence. As such, it is a major virulence determinant of P. gingivalis.

Neutrophil Elastase Mediates Innate Host Protection against Pseudomonas aeruginosa

According to the widely accepted view, neutrophil elastase (NE), a neutrophil-specific serine protease, is a major contributor to Pseudomonas aeruginosa infection-associated host tissue inflammation and damage, which in severe cases can lead to death. Herein, we provide for the first time compelling evidence that the host rather employs NE to protect itself against P. aeruginosa infection. Using a clinically relevant model of pneumonia, targeted deficiency in NE increased the susceptibility of mice to P. aeruginosa. We found that NE was required for maximal intracellular killing of P. aeruginosa by neutrophils. In investigating the mechanism of NE-mediated killing of P. aeruginosa, we found that NE degraded the major outer membrane protein F, a protein with important functions, including porin activity, maintenance of structural integrity, and sensing of host immune system activation. Consistent with this, the use of an isogenic mutant deficient in outer membrane protein F negated the role of NE in host defense against P. aeruginosa infection.

Immunomodulator Effect of Picroliv and its Potential in Treatment Against Resistant Plasmodium yoelii (MDR) Infection in Mice

The present study was envisaged to evaluate potential of combination therapy comprising of immunomodulator picroliv and antimalarial chloroquine against drug resistant Plasmodium yoelii (P. yoelii) infection in BALB/c mice. The immunomodulatory potential of picroliv was established by immunizing animals with model antigen along with picroliv. Immune response was assessed using T-cell proliferation assay and also by determining the antibody isotype-profile induced in the immunized mice. In the next set of experiment, prophylactic potential of picroliv to strengthen antimalarial properties of chloroquine against P. yoelii (MDR) infection in BALB/c mice was assessed. T-cell proliferation as well as antibody production study reveals that picroliv helps in evoking strong immuno-potentiating response against model antigen in the immunized mice. Co-administration of picroliv enhances efficacy of CHQ against experimental murine malaria. The activation of host immune system can increase the efficacy of chloroquine for suppression of drug resistant malaria infection in BALB/c mice.