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Bacterial colonization as a therapeutic approach. (a, left side of bladder) Intentional colonization of the bladder with an avirulent strain of bacteria (blue) may induce an asymptomatic bacteriuria state that inhibits the ability of virulent strains (black) to infect the bladder. This strategy may effectively prevent further urinary tract infections. (b, right side of bladder) Although the mechanisms of Bacillus Calmette–Guerin (BCG)-mediated tumor immunity are not well understood, BCG-specific CD8+ T cells play a critical role in the response to therapy. BCG (light blue) is instilled after tumors are resected (red is healing urothelium). Recently, we demonstrated that the presence of BCG in regional lymph nodes correlated with a robust BCG-specific CD8+ T-cell response. Whether this represents live BCG that have disseminated, or whether the BCG have been transported inside of a phagocytic cell remains to be determined. Dotted lines depict the hypothesis that BCG are carried to regional lymph nodes and presented to CD8+ T cells. Primed T cells then migrate to the bladder to participate in tumor immunity. ABU, asymptomatic bacteriuria; UPEC, uropathogenic Escherichia coli. Figures were generated with images from Servier Medical Art (www.servier.com), licensed under the Creative Commons Attribution 3.0 Unported License (http://creativecommons.org/license/by/3.0/).Download Power Point slide (311 KB)
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The pathogenesis of urinary tract infection and mechanisms of the protective effect of Bacillus Calmette-Guerin (BCG) therapy for bladder cancer highlight the importance of studying the bladder as a unique mucosal surface. Innate responses to bacteria are reviewed, and although our collective knowledge remains incomplete, we discuss how adaptive im...
Citations
... Особое строение зонтичных клеток -поверхностного слоя уротелия Плотные соединения между клетками уротелия, апикальные мембраны поверхностных клеток, покрытые «уротелиальными бляшками» (бляшки образованы мембранными белками -уроплакинами (UP1a, UP1b, UPII и UPIIIa), обеспечивают высокую гибкость и растяжимость эпителия мочевых путей, а также надежную барьерную функцию уротелия [21,22] Сила тока мочи во время микции Механическое удаление бактерий из мочевых путей [21] Слой муцина Слой гликозаминогликанов, препятствующий бактериальному доступу к поверхности уротелиальной клетки [21] Секреторный иммуноглобулин А Продуцируется в тканях слизистой оболочки мочевых путей и нейтрализует патогены и токсины [23] β-дефензины Относятся к группе катионных антимикробных пептидов, которые при взаимодействии с анионными липидами мембраны бактериальных клеток приводят к образованию мультимерных пор и повышению проницаемости мембраны. В результате бактериальная клетка теряет жизненно важное содержимое и погибает [24] Кателицидины Группа антимикробных пептидов, которые способствуют образованию трансмембранных пор в липидных биослоях клеточной мембраны микробной клетки. ...
... Особое строение зонтичных клеток -поверхностного слоя уротелия Плотные соединения между клетками уротелия, апикальные мембраны поверхностных клеток, покрытые «уротелиальными бляшками» (бляшки образованы мембранными белками -уроплакинами (UP1a, UP1b, UPII и UPIIIa), обеспечивают высокую гибкость и растяжимость эпителия мочевых путей, а также надежную барьерную функцию уротелия [21,22] Сила тока мочи во время микции Механическое удаление бактерий из мочевых путей [21] Слой муцина Слой гликозаминогликанов, препятствующий бактериальному доступу к поверхности уротелиальной клетки [21] Секреторный иммуноглобулин А Продуцируется в тканях слизистой оболочки мочевых путей и нейтрализует патогены и токсины [23] β-дефензины Относятся к группе катионных антимикробных пептидов, которые при взаимодействии с анионными липидами мембраны бактериальных клеток приводят к образованию мультимерных пор и повышению проницаемости мембраны. В результате бактериальная клетка теряет жизненно важное содержимое и погибает [24] Кателицидины Группа антимикробных пептидов, которые способствуют образованию трансмембранных пор в липидных биослоях клеточной мембраны микробной клетки. ...
... Особое строение зонтичных клеток -поверхностного слоя уротелия Плотные соединения между клетками уротелия, апикальные мембраны поверхностных клеток, покрытые «уротелиальными бляшками» (бляшки образованы мембранными белками -уроплакинами (UP1a, UP1b, UPII и UPIIIa), обеспечивают высокую гибкость и растяжимость эпителия мочевых путей, а также надежную барьерную функцию уротелия [21,22] Сила тока мочи во время микции Механическое удаление бактерий из мочевых путей [21] Слой муцина Слой гликозаминогликанов, препятствующий бактериальному доступу к поверхности уротелиальной клетки [21] Секреторный иммуноглобулин А Продуцируется в тканях слизистой оболочки мочевых путей и нейтрализует патогены и токсины [23] β-дефензины Относятся к группе катионных антимикробных пептидов, которые при взаимодействии с анионными липидами мембраны бактериальных клеток приводят к образованию мультимерных пор и повышению проницаемости мембраны. В результате бактериальная клетка теряет жизненно важное содержимое и погибает [24] Кателицидины Группа антимикробных пептидов, которые способствуют образованию трансмембранных пор в липидных биослоях клеточной мембраны микробной клетки. ...
I.N. ZAKHAROVA1, I.M. OSMANOV2, E.B. MACHNEVA3, E.B. MUMLADZE1, A.N. KASYANOVA1, M.P. AISANOVA1
1 Russian Medical Academy of Continuing Vocational Education of the Ministry of Health of the Russian Federation.
2 Bashlyaeva Children’s City Clinical Hospital of the Moscow Health Department
3 Russian Children’s Clinical Hospital, Pirogov Russian National Research Medical University (RNRMU) of the Ministry of Health of Russia
FROM BACTERIURIA TO THE URINARY TRACT MICROBIOME: THE EVOLUTION OF THE VIEWS OF RESEARCHERS AND CLINICIANS
The preservation of the human urinary tract integrity in interaction with microorganisms depends on the balance of many
components: the viability of nonspecific protective factors of the urinary tract mucosa, the virulence factors of microorganisms,
the intensity of the innate immune response of the urinary tract tissue to the presence of microorganisms, the mutual impact
of the micro- and macro-organism upon each other that is directed towards creation of a normal microbiome, and not
inflammation. Most of these factors are genetically determined both by microorganisms and humans. The article presents
modern data of Russian and foreign literature devoted to the description of factors supporting the homeostasis of the urinary
tract in interacting with microorganisms. The authors emphasise a key role of these data in the practice of clinicians, including
paediatricians and paediatric nephrologists, family doctors.
Keywords: urinary tract infection, bacteriuria, uropathogens, urine microbiome, genome, cytokines, interleukins, pathogenicity
islands, virulence factors, Escherichia coli, Toll-like receptors.
... Inflammatory cytokines secreted as part of the immune response to infection have the potential to be useful diagnostic biomarkers (Ko et al, 1993;Rao et al, 2001;Frimpong et al, 2022). There is an established association between local inflammation and UTI severity and recurrence in humans and animal models (Czaja et al, 2009;Sivick et al, 2010;Ingersoll & Albert, 2013). Inflammation contributes to the development of the clinical symptoms of dysuria, urgency, and frequency during UTI (Brierley et al, 2020). ...
Recurrent urinary tract infection (rUTI) severely impacts postmenopausal women. The lack of rapid and accurate diagnostic tools is a major obstacle in rUTI management as current gold standard methods have >24-h diagnostic windows. Work in animal models and limited human cohorts have identified robust inflammatory responses activated during UTI. Consequently, urinary inflammatory cytokines secreted during UTI may function as diagnostic biomarkers. This study aimed to identify urinary cytokines that could accurately diagnose UTI in a controlled cohort of postmenopausal women. Women passing study exclusion criteria were classified into no UTI and active rUTI groups, and urinary cytokine levels were measured by immunoassay. Pro-inflammatory cytokines IL-8, IL-18, IL-1β, and monocyte chemoattractant protein-1 were significantly elevated in the active rUTI group, and anti-inflammatory cytokines IL-13 and IL-4 were elevated in women without UTI. We evaluated cytokine diagnostic performance and found that an IL-8, prostaglandin E2, and IL-13 multivariable model had the lowest misclassification rate and highest sensitivity. Our data identify urinary IL-8, prostaglandin E2, and IL-13 as candidate biomarkers that may be useful in the development of immunoassay-based UTI diagnostics.
... Intravesical BCG evokes a significant localized immunological response characterized by the influx of macrophages, dendritic cells and neutrophils into the bladder wall within hours of instillation (Simons et al., 2008). CD4 + and CD8 + T cells are also found in increased numbers in the urine and mucosa of BCG-treated patients (Boccafoschi et al., 1992;de Boer et al., 1993;Ingersoll and Albert, 2013). Highly elevated levels of urinary cytokines IL-2, IL-6, IL-8, IL-18, IL-1ra, IFN-γ, IL-12[p70], TNFa, GM-CSF and chemokines including monocyte chemoattractant protein (MCP)-1, MIP-1α, and interferon-inducible protein (IP)-10 are found following BCG treatment (Taniguchi et al., 1999;Redelman-Sidi et al., 2014). ...
... Highly elevated levels of urinary cytokines IL-2, IL-6, IL-8, IL-18, IL-1ra, IFN-γ, IL-12[p70], TNFa, GM-CSF and chemokines including monocyte chemoattractant protein (MCP)-1, MIP-1α, and interferon-inducible protein (IP)-10 are found following BCG treatment (Taniguchi et al., 1999;Redelman-Sidi et al., 2014). As BCG infusions continue during induction, chemokine signaling further increases the recruitment of monocytes and neutrophils and the release of pro inflammatory cytokines to sustain a significant inflammatory response that is key to BCG efficacy and has the potential to sensitize bladderinnervating afferents (Simons et al., 2008;Ingersoll and Albert, 2013). However, whilst it seems logical to assume that inflammation induced sensitization of bladder-innervating afferent nerve endings is a crucial conduit of BCG induced LUTS, no studies have so far directly investigated if BCG-induced inflammation evokes bladder afferent hypersensitivity. ...
Non-muscle invasive bladder cancer (NMIBC) accounts for ~70–75% of total bladder cancer tumors and requires effective early intervention to avert progression. The cornerstone of high-risk NMIBC treatment involves trans-urethral resection of the tumor followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. However, BCG therapy is commonly accompanied by significant lower urinary tract symptoms (LUTS) including urinary urgency, urinary frequency, dysuria, and pelvic pain which can undermine treatment adherence and clinical outcomes. Despite this burden, the mechanisms underlying the development of BCG-induced LUTS have yet to be characterized. This review provides a unique perspective on the mechanisms thought to be responsible for the development of BCG-induced LUTS by focussing on the sensory nerves responsible for bladder sensory transduction. This review focuses on how the physiological response to BCG, including inflammation, urothelial permeability, and direct interactions between BCG and sensory nerves could drive bladder afferent sensitization leading to the development of LUTS. Additionally, this review provides an up-to-date summary of the latest clinical data exploring interventions to relieve BCG-induced LUTS, including therapeutic targeting of bladder contractions, inflammation, increased bladder permeability, and direct inhibition of bladder sensory signaling. Addressing the clinical burden of BCG-induced LUTS holds significant potential to enhance patient quality of life, treatment compliance, and overall outcomes in NMIBC management. However, the lack of knowledge on the pathophysiological mechanisms that drive BCG-induced LUTS has limited the development of novel and efficacious therapeutic options. Further research is urgently required to unravel the mechanisms that drive BCG-induced LUTS.
... These strategies involve the presence of a thick mucin barrier, regular urination, and the secretion of antibacterial agents, such as β-defensins and cathelicidin [71]. Conversely, the bladder maintains an immunosuppressive environment to avoid undesired immune responses [71,72]. Furthermore, bladder tumors' microenvironments are immunosuppressive, besides leading to tumor-infiltrating lymphocytes' (TILs) deficiency in effectively ruling out tumor cells [73]. ...
This study assessed the safety and efficacy of OncoTherad® (MRB-CFI-1) nanoimmunotherapy for non-muscle invasive bladder cancer (NMIBC) patients unresponsive to Bacillus Calmette-Guérin (BCG) and explored its mechanisms of action in a bladder cancer microenvironment. A single-arm phase I/II study was conducted with 44 patients with NMIBC who were unresponsive to BCG treatment. Primary outcomes were pathological complete response (pCR) and relapse-free survival (RFS). Secondary outcomes comprised response duration and therapy safety. Patients’ mean age was 65 years; 59.1% of them were refractory, 31.8% relapsed, and 9.1% were intolerant to BCG. Moreover, the pCR rate after 24 months reached 72.7% (95% CI), whereas the mean RFS reached 21.4 months. Mean response duration in the pCR group was 14.3 months. No patient developed muscle-invasive or metastatic disease during treatment. Treatment-related adverse events occurred in 77.3% of patients, mostly grade 1–2 events. OncoTherad® activated the innate immune system through toll-like receptor 4, leading to increased interferon signaling. This activation played a crucial role in activating CX3CR1+ CD8 T cells, decreasing immune checkpoint molecules, and reversing immunosuppression in the bladder microenvironment. OncoTherad® has proved to be a safe and effective therapeutic option for patients with BCG-unresponsive NMIBC, besides showing likely advantages in tumor relapse prevention processes.
... [118][119][120] Micropinocytosis allows BC cells to take in BCG, whereas normal urothelium cells have a much harder time doing so. [121][122][123] As a result, BCG will be able to activate many different types of immune cells by inducing both adaptive as well as innate immunological responses. [124][125][126] It has been determined that BCG can trigger apoptosis [127][128][129] and cellular oxidative stress, [130][131][132] both mechanisms that can directly eliminate BC cells. ...
Bladder cancer (BC) accounts for roughly 3% of all cancer diagnoses in developed countries. The prognosis could be improved significantly if the cancer is detected and classified as either muscle‐invasive bladder cancer (MIBC) or non‐muscle‐invasive bladder cancer (NMIBC) as promptly as possible. A potential ray of hope for the treatment of BC has emerged with the rapid development of nanomedicine and microRNAs (miRNAs), which promise to have fewer adverse effects, more tumor‐inhibitory effects, and decreased drug resistance. The complex interplay between hereditary and environmental variables is the root cause of this malignancy. Gene expression can be regulated by miRNAs, which are small, non‐coding RNAs that can either prevent the translation of protein‐coding genes or cleave RNA transcripts at certain locations. Elevated genomics has enabled a more extensive investigation of miRNAs whose expression is considerably different in BC patients compared to healthy volunteers or between BC tumor tissues and peripheral tissues. miRNAs have recently been discovered to be important regulators of BC cell carcinogenicity. Inaccurate diagnoses and prolonged treatment delays are more likely to occur due to the current diagnostic process such as lack of sensitivity and specificity and poor image quality. Patients now have access to a plethora of treatment options, including but not limited to surgery, chemotherapy, immunotherapy, gene therapy, and other innovative medicines, and in some cases, combination therapies. BC is one of the deadliest and most disabling malignancies affecting the urinary tract. Cancer of the urinary bladder has a terrible propensity for being fatal. BC is an intricate illness whose development can be affected by multiple parameters. Standard treatments for BC increase prognosis and survival, although recurrence is a major concern for patients. miRNAs are naturally occurring, small RNA molecules that have been linked to cancer through their expression being dysregulated. miRNAs modulate many cellular activities including proliferation, migration, differentiation, and apoptosis. MiRNA dysregulation is recognized in BC, and miRNAs are used as diagnostic and prognostic indicators. However, this manuscript discusses the recent progress made in nanomedicine and the function of miRNAs in the pathogenesis and targeted therapy of BC.
... BCG works by inducing nonspecific immune reactions and mediating antitumor effects through the activation of inflammatory responses. CD4 + and CD8 + lymphocytes, NK cells, granulosa cells, giant cells, and dendritic cells (DCs) may be involved (118)(119)(120)(121). In a mouse model of subcutaneously implanted CT26 colon cancer cells, it was found that pretreatment with Lactobacillus plantarum (KC836552.1) ...
The gut microbiota is not just a simple nutritional symbiosis that parasitizes the host; it is a complex and dynamic ecosystem that coevolves actively with the host and is involved in a variety of biological activities such as circadian rhythm regulation, energy metabolism, and immune response. The development of the immune system and immunological functions are significantly influenced by the interaction between the host and the microbiota. The interactions between gut microbiota and cancer are of a complex nature. The critical role that the gut microbiota plays in tumor occurrence, progression, and treatment is not clear despite the already done research. The development of precision medicine and cancer immunotherapy further emphasizes the importance and significance of the question of how the microbiota takes part in cancer development, progression, and treatment. This review summarizes recent literature on the relationship between the gut microbiome and cancer immunology. The findings suggest the existence of a “symbiotic microecosystem” formed by gut microbiota, metabolome, and host immunome that is fundamental for the pathogenesis analysis and the development of therapeutic strategies for cancer.
... It should be noted that scarce scientifi c literature has been published on experimental studies and clinical observations regarding the effectiveness of spore probiotics in the treatment of urinary tract infections. In particular, it was shown that the elimination of uropathogenic microorganisms from the vagina of patients with nosocomial urinary tract infections significantly increased under the action of Bactisporin formulation of probiotic strain B. subtilis [17]. Th e use of another probiotic strain, B. coagulans UniqueIS-2 (Unique Biotech Limited, India), along with antibiotic therapy in the treatment of patients with bacterial vaginosis led to a decrease in the disease relapse and the disappearance of concomitant symptoms such as discharge, burning, urination, itching, and soreness [18]. ...
... We have not established the mechanisms of therapeutic action, including the antibacterial action of the strains B. subtilis and B. megatherium, which compose the probiotic composition under study. However, it has long been known that the antimicrobial effi cacy of bacilli against uropathogenic microorganisms is associated with their ability to produce metabolites, primarily bacteriocins [17,19,[32][33][34][35]. For example, Subtilosin A, which is produced by B. amyloliquefaciens and B. subtilis, eff ectively inhibited the growth of Gardnerella vaginalis, the causative agent of bacterial vaginosis and other human uropathogens through the induction of cells of transitional pores in the cytoplasmic membrane, which led to the leakage of intracellular ions and ATP and cell death [33,[36][37][38]. ...
... Th e cell-free supernatant of the B. subtilis strain R-18 also has an antimicrobial eff ect on S. marcescens, which causes various nosocomial infections (mostly urinary tract infections) and shows increased resistance to conventional antibiotics [35]. Metabolites of B. subtilis have been shown to reduce the resistance of uropathogenic microfl ora to antibiotics [17]. Lactosporin B. coagulans ATCC 7050 [32] and Subtilosin bacilli in the composition of vaginal hydrogel [39] have been used for the treatment of patients with bacterial vaginosis. ...
The purpose of this study was to investigate the antimicrobial and immunomodulatory action of a probiotic composition of Bacillus subtilis and B. megatherium strains (UnicaUro, Sirion (Ukraine)) for experimental bacterial vaginitis. Methods. Experimental studies were conducted on female BALB/c mice; we used Staphylococcus aureus strain B-918 (ATCC 6538) to induce bacterial vaginitis. The strain was vaginally introduced into mice before treatment with probiotic bacteria. In the vagina of mice, aerobic and optionally anaerobic bacteria, including representatives of the genera Staphylococcus, Streptococcus, Lactobacillus, Bifidobacterium, Pseudomonas, coliform bacteria, and microscopic fungi were identified in different periods of observation using generally accepted microbiological methods. Serum antibody titer to S. aureus was determined by the bacterial agglutination reaction. The phagocytic activity and oxygen-dependent bactericidal activity of peritoneal exudate macrophages (PEM) were evaluated using generally accepted immunological methods. Results. The formation of bacterial vaginitis in the BALB/c mice line infected with S. aureus B-918 (ATCC 6538) was evidenced by the appearance of external clinical manifestations of the infectious and inflammatory process against the background of the increased number of aerobic and optionally anaerobic microorganisms, including representatives of the genus Staphylococcus and Streptococcus, microscopic fungi, and decreased number of lactobacilli in different observation periods. The probiotic introduction to mice with bacterial vaginitis led to a dynamic change in the vaginal microbiota: the number of aerobic and optionally anaerobic microorganisms decreased, primarily due to the normalization of the number of representatives of Staphylococcus genus accompanied by a decrease in the antibody titer to staphylococcus in the blood serum. The effective therapeutic action of the probiotic was confirmed by the gradual disappearance of the external clinical signs of the infectious-inflammatory process in the vagina against the background of the functional activity of PEM. Conclusions. The probiotic composition of B. subtilis and B. megatherium (UnicaUro, Sirion, Ukraine) is a promising antimicrobial formulation that may be used in the treatment of bacterial vaginitis; however, further studies are required to confirm its therapeutic, antimicrobial, and immunomodulatory efficacy.
... These strategies include a thick mucin barrier, urination, and secretion of antibacterial agents such as β-defensins and cathelicidin (34) . On the other hand, bladder has an immunosuppressive environment to prevent undesirable immune responses (34,35) . In addition, the bladder tumor microenvironment is immunosuppressive. ...
Background: This study characterized and compared the molecular profiles of CX3C chemokine receptor 1 (CX3CR1, a marker of T-cell differentiation), Toll-like receptor 4 (TLR4)-mediated interferon signaling pathway, and immune checkpoints in the different histological stages of non-muscle invasive bladder cancer (NMIBC), aiming the investigation of these biomarkers as a criterion of clinical response to immunotherapy. Methods: Seventy-five formalin-fixed paraffin-embedded samples of bladder were obtained from 34 to 96-year-old patients (mean 65 years) with NMIBC diagnosis in University of Campinas (UNICAMP) and Paulinia Municipal Hospital/ Brazil. Subsequently, the samples were divided into 3 groups (n= 25 samples per group): pTis group, high-grade pTa group, and pT1 group; and submitted to immunohistochemistry analysis: TLR4-mediated IFN-γ production signaling pathway (TRIF, TBK1, IRF-3, IFN-γ), CX3CR1+CD8+ T-cells, immune checkpoints (PD-1/PD-L1 and CTLA-4), and regulatory T (Treg) cells (FOXP3). The retrospective anonymous study was approved by the local ethics committee (Clinical Trial: RBR-6swqd2). Results: pTis group showed the lowest activation of TLR4-mediated IFN-γ signaling pathway when compared (p<0.01) to high-grade pTa and pT1 groups. Both the immunoreaction intensity and positive cells percentage were lower (p<0.01) for TLR4, TRIF, IRF-3, and IFN-γ in the pTis group with respect to other groups. No statistical difference was found between high-grade pTa and pT1 groups for these biomarkers. Likewise, CX3CR1 immunoreactivities were remarkably lower (p<0.01) in the pTis group in comparison with high-grade pTa and pT1 groups, which did not show statistical differences between them. Furthermore, immune checkpoints (PD-1/PD-L1 and CTLA4) and FOXP3+ Treg cells immunoreactivities were significantly higher (p<0.01) in the high-grade pTa and pT1 compared to the pTis group. Conclusions: Our data demonstrated that pTis stage was characterized by an immunosuppressive microenvironment in comparison with pTa and pT1 stages, showing decreased TLR4-mediated interferon signaling pathway and low activation of CX3CR1+CD8+ T-cells; which implies in low sensitivity to immunotherapy. The larger number of FOXP3+ Treg cells in pTa and pT1 was correlated with intensified immune checkpoints immunoreactivities, indicating higher sensitivity to immunotherapy. Finally, these biomarkers may be useful in the clinical management of patients with NMIBC.
... The urinary microbiome influences the local bladder immune microenvironment and influences innate and adaptive immunity [59]. There is wide variation in response to BCG therapy from one patient to another with NMIBC. ...
Bladder cancer is the 10th most common cancer worldwide. Approximately 75% of patients with bladder cancer will present with non-muscle invasive disease. Patients are usually treated with transurethral resection of bladder tumor (TURBT), in addition to adjuvant intravesical therapy (chemotherapy or anti-cancer immunotherapy with Bacillus Calmette Guerin- BCG) for those at intermediate-risk and high-risk of recurrence and progression. For many years, urine has been thought to be “sterile”; however, advanced microbiological and molecular techniques, including 16S ribosomal RNA (16S rRNA) sequencing, have negated that previous paradigm and confirmed the presence of a urinary microbiome. The urinary microbiome has been associated with several urological diseases, including interstitial cystitis, urgency urinary incontinence, neurogenic bladder dysfunction, and others. More recently, many reports are emerging about the role of the urinary microbiome in urothelial carcinogenesis, including gender disparity in bladder cancer and responses to treatments. The urinary microbiome may serve as a biomarker that can help with risk stratification as well as prediction of the response to intravesical therapies. However, the microbiome literature has been hampered by the lack of a unified standardized methodology for sample collection, type, preservation, processing, as well as bioinformatics analysis. Herein we describe and critique the literature on the association between urinary microbiome and bladder cancer and highlight some of the future directions.
... Thus, we can consider that the direct stimulation of the immune response on the urothelium through intravesical (IVES) treatment, as after a transurethral resection procedure, could be as effective or more effective than immunization by other routes of administration. In this case, the induction of a local response associated with a local inflammatory process, triggered by the surgical procedure itself, could disrupt bladder immune tolerance and potentialize the antitumor immune response [5,11]. However, the physiological characteristics of the bladder generate additional challenges for the introduction and maintenance of antigens in the vesicle for as long as necessary for the activation of an anti-tumor immune response. ...
Background
Activating the immune system for therapeutic benefit has long been a goal in immunology, especially in cancer treatment, but the low immunogenicity of antitumor vaccines remains a limiting factor in the fight against malignant neoplasms. The increase in the immunogenicity of weak antigens using biodegradable polymers, such as chitosan, has been observed in the field of cancer immunotherapy. However, the effects of the vaccine using a combination of tumor cells and a thermoreversible delivery system based on chitosan in bladder cancer models, mainly using the intravesical route to stimulate the antitumor immune response, are unknown. We propose to evaluate the efficacy of a polymeric gel matrix (TPG) formed by poloxamer 407 and chitosan, associated with MB49 cells, as an intravesical antitumor vaccine using a C57BL/6 murine model of bladder urothelial carcinoma. The effectiveness of immunization was analyzed with the formation of three experimental groups: Control, TPG and TPG + MB49. In the vaccination phase, the TPG + MB49 group underwent a traumatic injury to the bladder wall with immediate intravesical instillation of the vaccine compound containing MB49 cells embedded in TPG. The TPG group was subjected to the same procedures using the compound containing the gel diluted in medium, and the control group using only the medium. After 21 days, the animals were challenged with tumor induction.
Results
In vitro tests showed loss of viability and inability to proliferate after exposure to TPG. In vivo tests showed that animals previously immunized with TPG + MB49 had higher cumulative survival, as well as significantly lower bladder weight and size in contrast to the other two groups that did not show a statistically different tumor evolution. In addition, the splenocytes of these animals also showed a higher rate of antitumor cytotoxicity in relation to the TPG and control groups.
Conclusions
We can conclude that MB49 cells embedded in a polymeric thermoreversible gel matrix with chitosan used in the form of an intravesical vaccine are able to stimulate the immune response and affect the development of the bladder tumor in an orthotopic and syngeneic C57BL/6 murine model.
