RESUMEN
PURPOSE: We report the results of a randomized phase II trial of imiquimod, a topical immune-response modulator versus imiquimod plus a 9-valent human papillomavirus (HPV) vaccine (9vHPV) versus clinical surveillance in cervical intraepithelial neoplasia (CIN2/3) patients. PATIENTS AND METHODS: We randomly allocated 133 patients with untreated CIN2/3 in equal proportions to a 4-month treatment with self-applied vaginal suppositories containing imiquimod (Arm B) or imiquimod plus a 9vHPV (Arm C) versus clinical surveillance (Arm A). The main outcome was efficacy, defined as histologic regression to CIN1 or less. Secondary outcomes were HPV clearance and tolerability. Exploratory objectives included the comparison of cervical CD4/CD8 T-cell infiltration at baseline, mid-study, and posttreatment by flow cytometry among study arms. RESULTS: Of the 114 evaluable patients 77% and 23% harbored CIN2 and CIN3, respectively. Regression to CIN1 or less was observed in 95% of patients in the imiquimod group (Arm B) compared with 79% in the control/surveillance (Arm A); P = 0.043 and 84% in the imiquimod+9vHPV group (Arm C; P = 0.384 vs. Arm A). Neither of the treatment-arm differences from Arm A reached the prespecified α = 0.025 significance level. No significant differences were noted in the secondary outcome of rate of HPV clearance. The number of tissue-resident memory CD4/CD8 T cells in cytobrush samples demonstrated a >5-fold increase in Arm B/imiquimod when compared with Arm A/surveillance (P < 0.01). In contrast, there was no significant difference in T-cell responses among participants in Arm C when compared with Arm A. Imiquimod treatment was well tolerated. CONCLUSIONS: Although imiquimod induced a higher regression to CIN1 or less and significant increases in CD4/CD8 T cells infiltrating the cervix, it did not meet its prespecified statistical outcome for efficacy. A higher regression rate than expected was observed in the surveillance arm of this prospective trial. Future clinical trials with imiquimod targeting CIN3 patients are warranted.
Asunto(s)
Imiquimod , Infecciones por Papillomavirus , Vacunas contra Papillomavirus , Displasia del Cuello del Útero , Neoplasias del Cuello Uterino , Humanos , Imiquimod/administración & dosificación , Femenino , Vacunas contra Papillomavirus/administración & dosificación , Adulto , Displasia del Cuello del Útero/inmunología , Displasia del Cuello del Útero/tratamiento farmacológico , Displasia del Cuello del Útero/patología , Displasia del Cuello del Útero/virología , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/complicaciones , Infecciones por Papillomavirus/virología , Persona de Mediana Edad , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/patología , Neoplasias del Cuello Uterino/virología , Aminoquinolinas/administración & dosificación , Aminoquinolinas/efectos adversos , Aminoquinolinas/uso terapéutico , Resultado del Tratamiento , Linfocitos T CD8-positivos/inmunología , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/patología , Lesiones Precancerosas/inmunología , Clasificación del Tumor , Adulto JovenRESUMEN
Discoid lupus erythematosus and oral lichen planus are chronic systemic immune system-mediated diseases with unclear etiology and pathogenesis. The oral mucosa is the common primary site of pathogenesis in both, whereby innate and adaptive immunity and inflammation play crucial roles. The clinical manifestations of discoid lupus erythematosus on the oral mucosa are very similar to those of oral lichen planus; therefore, its oral lesion is classified under oral lichenoid lesions. In practice, the differential diagnosis of discoid lupus erythematosus and oral lichen planus has always relied on the clinical manifestations, with histopathological examination as an auxiliary diagnostic tool. However, the close resemblance of the clinical manifestations and histopathology proves challenging for accurate differential diagnosis and further treatment. In most cases, dentists and pathologists fail to distinguish between the conditions during the early stages of the lesions. It should be noted that both are considered to be precancerous conditions, highlighting the significance of early diagnosis and treatment. In the context of unknown etiology and pathogenesis, we suggest a serological and genetic diagnostic method based on TNF-α and IL-10. These are the two most common cytokines produced by the innate and adaptive immune systems and they play a fundamental role in maintaining immune homeostasis and modulating inflammation. The prominent variability in their expression levels and gene polymorphism typing in different lesions compensates for the low specificity of current conventional diagnostic protocols. This new diagnostic scheme, starting from the immunity and inflammation of the oral mucosa, enables simultaneous comparison of discoid lupus erythematosus and oral lichen planus. With relevant supportive evidence, this information can enhance physicians' understanding of the two diseases, contribute to precision medicine, and aid in prevention of precancerous conditions.
Asunto(s)
Interleucina-10 , Liquen Plano Oral , Lupus Eritematoso Discoide , Lesiones Precancerosas , Factor de Necrosis Tumoral alfa , Genotipo , Humanos , Pruebas Inmunológicas , Inflamación , Interleucina-10/genética , Interleucina-10/inmunología , Liquen Plano Oral/genética , Liquen Plano Oral/inmunología , Lupus Eritematoso Discoide/genética , Lupus Eritematoso Discoide/inmunología , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
BACKGROUND/AIM: We previously observed higher prevalence of high-grade pancreatic intraepithelial neoplasia (PanIN) in LSL-KrasG12D/+; Pdx1Cre/+ (KC-Crmp4wild) mice than LSL-KrasG12D/+; Pdx1Cre/+; Crmp4-/- (KC-Crmp4-/-) mice. This study investigated the relationship between collapsin response mediator protein 4 (CRMP4) and immune cell infiltration in pancreatic cancer. MATERIALS AND METHODS: PanIN was induced by intraperitoneal injection of caerulein into KC-Crmp4wild and KC-Crmp4-/- mice, and immune cells in PanIN lesions were compared. Subcutaneous tumors were created by injecting Pan02 cells, and tumor diameter was compared between Crmp4wild and Crmp4-/- mice every 7 days. Peritumoral immune cells were examined immunohisto chemically. RESULTS: High-grade PanIN in KC mice showed statistically significantly high expression of CD163 (p=0.031) and CD11b (p=0.027). Following subcutaneous injection of Pan02 cells, tumor diameter was greater in Crmp4wild mice than Crmp4-/- mice. Crmp4wild mice exhibited higher CD163 and CD11b expression than Crmp4-/- mice in tumors (p<0.001). CONCLUSION: CRMP4 might promote pancreatic cancer by up-regulating M2 macrophages and myeloid-derived suppressor cells.
Asunto(s)
Macrófagos/metabolismo , Células Supresoras de Origen Mieloide/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neoplasias Pancreáticas/metabolismo , Animales , Antígenos CD/metabolismo , Antígenos de Diferenciación Mielomonocítica/metabolismo , Antígeno CD11b/metabolismo , Línea Celular Tumoral , Modelos Animales de Enfermedad , Ratones , Proteínas del Tejido Nervioso/deficiencia , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patología , Receptores de Superficie Celular/metabolismo , Carga TumoralRESUMEN
Breast cancer (BC) prevention remains the ultimate cost-effective method to reduce the global burden of invasive breast cancer (IBC). To date, surgery and chemoprevention remain the main risk-reducing modalities for those with hereditary cancer syndromes, as well as high-risk non-hereditary breast lesions such as ADH, ALH, or LCIS. Ductal carcinoma in situ (DCIS) is a preinvasive malignant lesion of the breast that closely mirrors IBC and, if left untreated, develops into IBC in up to 50% of lesions. Certain high-risk patients with DCIS may have a 25% risk of developing recurrent DCIS or IBC, even after surgical resection. The development of breast cancer elicits a strong immune response, which brings to prominence the numerous advantages associated with immune-based cancer prevention over drug-based chemoprevention, supported by the success of dendritic cell vaccines targeting HER2-expressing BC. Vaccination against BC to prevent or interrupt the process of BC development remains elusive but is a viable option. Vaccination to intercept preinvasive or premalignant breast conditions may be possible by interrupting the expression pattern of various oncodrivers. Growth factors may also function as potential immune targets to prevent breast cancer progression. Furthermore, neoantigens also serve as effective targets for interception by virtue of strong immunogenicity. It is noteworthy that the immune response also needs to be strong enough to result in target lesion elimination to avoid immunoediting as it may occur in IBC arising from DCIS. Overall, if the issue of vaccine targets can be solved by interrupting premalignant lesions, there is a potential to prevent the development of IBC.
Asunto(s)
Antígenos de Neoplasias/inmunología , Carcinoma de Mama in situ/terapia , Neoplasias de la Mama/terapia , Vacunas contra el Cáncer/uso terapéutico , Carcinoma Intraductal no Infiltrante/terapia , Lesiones Precancerosas/terapia , Microambiente Tumoral/inmunología , Vacunación , Animales , Antígenos de Neoplasias/metabolismo , Carcinoma de Mama in situ/inmunología , Carcinoma de Mama in situ/metabolismo , Carcinoma de Mama in situ/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Vacunas contra el Cáncer/efectos adversos , Carcinoma Intraductal no Infiltrante/inmunología , Carcinoma Intraductal no Infiltrante/metabolismo , Carcinoma Intraductal no Infiltrante/patología , Progresión de la Enfermedad , Femenino , Humanos , Invasividad Neoplásica , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/metabolismo , Lesiones Precancerosas/patologíaRESUMEN
Epithelial cells have an ability termed 'cell competition', which is an immune surveillance-like function that extrudes precancerous cells from the epithelial layer, leading to apoptosis and clearance. However, it remains unclear how epithelial cells recognize and extrude transformed cells. Here, we discovered that a PirB family protein, leukocyte immunoglobulin-like receptor B3 (LILRB3), which is expressed on non-transformed epithelial cells, recognizes major histocompatibility complex class I (MHC class I) that is highly expressed on transformed cells. MHC class I interaction with LILRB3 expressed on normal epithelial cells triggers an SHP2-ROCK2 pathway that generates a mechanical force to extrude transformed cells. Removal of transformed cells occurs independently of natural killer (NK) cell or CD8+ cytotoxic T cell-mediated activity. This is a new mechanism in that the immunological ligand-receptor system generates a mechanical force in non-immune epithelial cells to extrude precancerous cells in the same epithelial layer.
Asunto(s)
Antígenos CD/metabolismo , Apoptosis , Competencia Celular , Células Epiteliales/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Neoplasias Pulmonares/metabolismo , Lesiones Precancerosas/metabolismo , Receptores Inmunológicos/metabolismo , Animales , Antígenos CD/genética , Subunidad alfa 1 del Factor de Unión al Sitio Principal/metabolismo , Perros , Células Epiteliales/inmunología , Células Epiteliales/patología , Células HaCaT , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Células de Riñón Canino Madin Darby , Mecanotransducción Celular , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Proteína Tirosina Fosfatasa no Receptora Tipo 11/metabolismo , Células RAW 264.7 , Receptores Inmunológicos/genética , Estrés Mecánico , Quinasas Asociadas a rho/metabolismoRESUMEN
Cancer vaccines are a type of immune therapy that seeks to modulate the host's immune system to induce durable and protective immune responses against cancer-related antigens. The little clinical success of therapeutic cancer vaccines is generally attributed to the immunosuppressive tumor microenvironment at late-stage diseases. The administration of cancer-preventive vaccination at early stages, such as pre-malignant lesions or even in healthy individuals at high cancer risk could increase clinical efficacy by potentiating immune surveillance and pre-existing specific immune responses, thus eliminating de novo appearing lesions or maintaining equilibrium. Indeed, research focus has begun to shift to these approaches and some of them are yielding encouraging outcomes.
Asunto(s)
Vacunas contra el Cáncer/uso terapéutico , Neoplasias/prevención & control , Lesiones Precancerosas/tratamiento farmacológico , Humanos , Estadificación de Neoplasias , Neoplasias/inmunología , Neoplasias/patología , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Microambiente TumoralRESUMEN
BACKGROUND: The association of Helicobacter pylori-negative gastritis with lymphoid follicles (LFs) in children is still unclear. Therefore, we aimed to investigate the natural history and significance of H. pylori-negative gastritis with LFs in children. METHODS: We identified children with histologically proven H. pylori-negative gastritis with LFs between June 2014 and January 2017. The children were invited for a follow-up examination. The clinical, endoscopic, and histological findings of the index esophagogastroduodenoscopy (EGD) were revised and compared to the follow-up findings. RESULTS: A total of 754 children underwent EGD. Among the 48 children diagnosed with H. pylori-negative gastritis, 17 (35.41%) had gastric LFs. Eight agreed to participate in the study. The mean follow-up was 25.58 ± 4.52 (range, 20.53-35.73) months. Three children still had histologic findings of chronic gastritis with LFs. Four children had resolution of the gastritis but still had LFs, and 1 patient had resolution of both the gastritis and LFs. CONCLUSION: LFs were still present in children with H. pylori-negative gastritis after a mean follow-up of 2 years, and in some children, despite resolution of the gastritis. Therefore, this histological finding might be a non-pathological feature in children and does not need any contribution or follow-up.
Asunto(s)
Gastritis , Tejido Linfoide , Adolescente , Biopsia , Niño , Preescolar , Progresión de la Enfermedad , Endoscopía del Sistema Digestivo , Femenino , Gastritis/diagnóstico , Gastritis/etiología , Gastritis/inmunología , Gastritis/patología , Infecciones por Helicobacter/complicaciones , Helicobacter pylori , Humanos , Tejido Linfoide/inmunología , Tejido Linfoide/patología , Masculino , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/etiología , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Estudios Prospectivos , Estómago/inmunología , Estómago/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Oral Potentially Malignant Disorders (OPMD) have a non-negligible malignant transformation rate of up to 8%. Loss of heterozygosity (LOH) in critical chromosomal loci has proven to be the most effective marker in defining the risk of transformation and it is found in about 28% of OPMD and may therefore identify patients carrying higher risk. To date, clinical management of OPMD is limited to surgical excision and clinical surveillance, which however do not fully prevent oral cancer development. Immune system has been shown to play a key role in transformation surveillance mechanism and an immunosuppressive imbalance may be responsible for progression to cancer. Given all these considerations, we designed a clinical trial with the aim to prevent OPMD neoplastic transformation and revert the LOH status. METHODS: This is a phase II, open label, single arm, multicentric trial involving Italian referral centres and expected to enrol 80 patients out of a total of 175 screened. Patients who meet all inclusion criteria and test positive for LOH after an incisional biopsy of the OPMD will undergo a short course of immunotherapy with 4 administration of avelumab. After 6 months since treatment start, resection of the entire OPMD will be performed and LOH assessment will be repeated. The follow-up for malignant transformation and safety assessment will last 30 months from the end of treatment, for a total planned study duration of approximately 5.5 years. DISCUSSION: Restoring the activity of immune system through checkpoint inhibitor may play a crucial role against malignant transformation of OPMD by reverting the balance in favour of immune control and preventing cancer occurrence. TRIAL REGISTRATION: This trial was prospectively registered in ClinicalTrials.gov as NCT04504552 on 7th August 2020.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/administración & dosificación , Neoplasias de la Boca/epidemiología , Lesiones Precancerosas/tratamiento farmacológico , Escape del Tumor/efectos de los fármacos , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Ensayos Clínicos Fase II como Asunto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Italia/epidemiología , Pérdida de Heterocigocidad , Masculino , Neoplasias de la Boca/genética , Neoplasias de la Boca/inmunología , Neoplasias de la Boca/prevención & control , Estudios Multicéntricos como Asunto , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/mortalidad , Recurrencia , Escape del Tumor/genética , Escape del Tumor/inmunología , Adulto JovenRESUMEN
The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.
Asunto(s)
Adenocarcinoma in Situ/genética , Adenocarcinoma del Pulmón/genética , Carcinogénesis/genética , Neoplasias Pulmonares/genética , Proteínas de Neoplasias/genética , Lesiones Precancerosas/genética , Transcriptoma , Adenocarcinoma in Situ/inmunología , Adenocarcinoma in Situ/patología , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Carcinogénesis/inmunología , Carcinogénesis/patología , Aberraciones Cromosómicas , Células Clonales , Variaciones en el Número de Copia de ADN , Metilación de ADN , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunidad Innata , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Proteínas de Neoplasias/inmunología , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Transducción de Señal , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Escape del Tumor/genética , Escape del Tumor/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Cervical cancer is the fourth most common cancer and fourth leading cause of cancer death among women worldwide. In low Human Development Index settings, it ranks second. Screening and surveillance involve the cytology-based Papanicolaou (Pap) test and testing for high-risk human papillomavirus (hrHPV). The Pap test has low sensitivity to detect precursor lesions, while a single hrHPV test cannot distinguish a persistent infection from one that the immune system will naturally clear. Furthermore, among women who are hrHPV-positive and progress to high-grade cervical lesions, testing cannot identify the ~20% who would progress to cancer if not treated. Thus, reliable detection and treatment of cancers and precancers requires routine screening followed by frequent surveillance among those with past abnormal or positive results. The consequence is overtreatment, with its associated risks and complications, in screened populations and an increased risk of cancer in under-screened populations. Methods to improve cervical cancer risk assessment, particularly assays to predict regression of precursor lesions or clearance of hrHPV infection, would benefit both populations. Here we show that women who have lower risk results on follow-up testing relative to index testing have evidence of enhanced T cell clonal expansion in the index cervical cytology sample compared to women who persist with higher risk results from index to follow-up. We further show that a machine learning classifier based on the index sample T cells predicts this transition to lower risk with 95% accuracy (19/20) by leave-one-out cross-validation. Using T cell receptor deep sequencing and machine learning, we identified a biophysicochemical motif in the complementarity-determining region 3 of T cell receptor ß chains whose presence predicts this transition. While these results must still be tested on an independent cohort in a prospective study, they suggest that this approach could improve cervical cancer screening by helping distinguish women likely to spontaneously regress from those at elevated risk of progression to cancer. The advancement of such a strategy could reduce surveillance frequency and overtreatment in screened populations and improve the delivery of screening to under-screened populations.
Asunto(s)
Alphapapillomavirus/inmunología , Detección Precoz del Cáncer , Genes Codificadores de la Cadena beta de los Receptores de Linfocito T , Prueba de Papanicolaou , Infecciones por Papillomavirus/diagnóstico , Lesiones Precancerosas/diagnóstico , Linfocitos T/inmunología , Neoplasias del Cuello Uterino/diagnóstico , Frotis Vaginal , Adulto , Alphapapillomavirus/genética , Alphapapillomavirus/patogenicidad , Regiones Determinantes de Complementariedad/genética , Femenino , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Pruebas de ADN del Papillomavirus Humano , Humanos , Aprendizaje Automático , Persona de Mediana Edad , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/virología , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/virología , Valor Predictivo de las Pruebas , Prueba de Estudio Conceptual , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de Riesgo , Linfocitos T/virología , Transcriptoma , Neoplasias del Cuello Uterino/inmunología , Neoplasias del Cuello Uterino/virologíaRESUMEN
The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Gammopatía Monoclonal de Relevancia Indeterminada/inmunología , Mieloma Múltiple/inmunología , Lesiones Precancerosas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Carcinogénesis , Proliferación Celular , Humanos , Activación de Linfocitos , Microambiente TumoralRESUMEN
OBJECTIVE: Deciphering the determinants of the intralesional immune reaction in cervical carcinogenesis may be conducive to improving the understanding of the disease and then improve outcomes. METHODS: Public gene-expression data and full clinical annotation were searched in Gene Expression Omnibus in the joint analysis of the array-based four eligible cohorts. The infiltrating estimation was quantified using microenvironment cell populations-counter algorithm and absolute-mode CIBERSORT and verified by flow cytometry analysis. An unsupervised classification on immune genes strongly associated with progression, designated by linear mixed-effects regression. We determined immune response and signaling features of the different developmental stages and immune phenotypes by functional annotation and systematically correlated the expression of immune checkpoints with cell-infiltrating characteristics. RESULTS: We identified the lesion-intrinsic immunosuppression mechanism was triggered at precancerous stages, such as genome instability and mutation, aerobic glycolysis, activation of proto-oncogene pathways and so forth. Predominant innate and adoptive cells were increasing from normalcy to cancer (B cell, total T cell, regulatory T cells [Tregs], monocytes, neutrophils, and M2-like macrophages) together with the decrease of CD4+ T cell and CD8+ T cell through the development of cervical cancer. Immune escape initiated on the expression of immunosuppressive molecules from high-grade squamous intraepithelial lesions (HSIL) and culminated in squamous cell carcinoma (SCC). Of note, the expression of immune checkpoints was escalated in the immune-hot and immune-warm phenotype largely encompassed by HSIL and SCC under the stress of both activated and suppressive immune responses. CONCLUSIONS: Immune surveillance is unleashing from low-grade squamous intraepithelial lesions onwards and immune-suppression mechanisms are triggered in HSIL. Thorough knowledge of the immune changing pattern during cervical tumorigenesis contributes to finding the potential therapeutic targets to susceptive patients towards immune checkpoints inhibitors.
Asunto(s)
Lesiones Precancerosas/inmunología , Microambiente Tumoral/inmunología , Neoplasias del Cuello Uterino/inmunología , Algoritmos , Carcinogénesis/inmunología , Carcinoma de Células Escamosas/etiología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Cuello del Útero/patología , Bases de Datos Genéticas , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Inestabilidad Genómica , Glucólisis , Humanos , Tolerancia Inmunológica/genética , Inmunidad Celular , Inmunofenotipificación , Monitorización Inmunológica , Mutación , Lesiones Precancerosas/etiología , Lesiones Precancerosas/genética , Lesiones Precancerosas/patología , Proto-Oncogenes Mas , Activación Transcripcional , Escape del Tumor/inmunología , Neoplasias del Cuello Uterino/etiología , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/patologíaRESUMEN
Cancer is one of the most serious diseases affecting health and the second leading cause of death worldwide. Despite the development of various therapeutic modalities to deal with cancer, limited improvement in overall survival of patients has been yielded. Since there is no certain cure for cancer, detection of premalignant lesions, and prevention of their progression are vital to the decline of high morbidity and mortality of cancer. Among approaches to cancer prevention, immunoprevention has gained further attention in recent years. Deep understanding of the tumor/immune system interplay and successful prevention of virally-induced malignancies by vaccines have paved the way toward broadening cancer immunoprevention application. The identification of tumor antigens in premalignant lesions was the turning point in cancer immunoprevention that led to designing preventive vaccines for various malignancies including multiple myeloma, colorectal, and breast cancer. In addition to vaccines, immune checkpoint inhibitors are also being tested for the prevention of oral squamous cell carcinoma (SCC), and imiquimod which is an established drug for the prevention of skin SCC, is a non-specific immunomodulator. Herein, to provide a bench-to-bedside understanding of cancer immunoprevention, we will review the role of the immune system in suppression and promotion of tumors, immunoprevention of virally-induced cancers, identification of tumor antigens in premalignant lesions, and clinical advances of cancer immunoprevention.
Asunto(s)
Neoplasias/prevención & control , Antígenos de Neoplasias/inmunología , Vacunas contra el Cáncer/inmunología , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Sistema Inmunológico/fisiología , Tolerancia Inmunológica , Factores Inmunológicos/uso terapéutico , Neoplasias/inmunología , Lesiones Precancerosas/inmunologíaRESUMEN
BACKGROUND: Solid organ transplant recipients are at increased risk for noncutaneous neoplasms, including colorectal cancer (CRC). We evaluated precancerous lesions detected by post-transplant surveillance colonoscopy to infer the rate at which new adenomas develop in this population. STUDY DESIGN: We reviewed all patients who underwent lung transplant between January 2013 and August 2017 at our institution. Those with post-transplant survival <1 year, personal history of CRC, previous lung transplant, and lack of pretransplant colonoscopy were excluded. RESULTS: During the study period, 411 patients underwent lung transplant; 237 met inclusion criteria. Median age at transplant was 63.6 (interquartile range [IQR] 59.2-68.3) years. Most recipients were immunosuppressed with a combination of prednisone, tacrolimus, and mycophenolate mofetil. At least 1 adenoma was found in 92 patients (38.8%) pretransplant and in 118 patients (49.8%) from 1 to 5 years post-transplant, with 68.6% identified at 1 year. Most adenomas were identified proximal to the splenic flexure. Multiple (≥3) adenomas were found in 31.4% of positive colonoscopies. Within 5 years after transplant, patients with a positive pretransplant colonoscopy had significantly more positive post-transplant colonoscopies than patients with a negative pretransplant colonoscopy (63.0% vs 41.4%, p < 0.001). No de novo CRC was identified. CONCLUSIONS: Lung transplant recipients have a significantly higher risk of adenoma formation than average-risk adults (25%-30% national detection rate). This increase occurs in the early post-transplant period (within 3 years). An enhanced CRC surveillance protocol for lung transplant recipients is needed.
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Adenoma/epidemiología , Neoplasias Colorrectales/prevención & control , Detección Precoz del Cáncer/estadística & datos numéricos , Trasplante de Pulmón/efectos adversos , Lesiones Precancerosas/epidemiología , Adenoma/diagnóstico , Adenoma/inmunología , Anciano , Colonoscopía/estadística & datos numéricos , Neoplasias Colorrectales/inmunología , Detección Precoz del Cáncer/métodos , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/prevención & control , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/diagnóstico , Lesiones Precancerosas/inmunología , Estudios Retrospectivos , Receptores de Trasplantes/estadística & datos numéricosRESUMEN
This study aimed to investigate the association of IgG glycosylation and esophageal precancerosis for squamous cell carcinoma and determine its role in inflammation. Primary glycans selected by the least absolute shrinkage and selection operator (LASSO) algorithm were validated using univariate and multivariate logistics models plus restricted cubic spline functions. In total, 24 direct glycans and 27 derived traits were detected, among which four glycans and three derived traits were primarily selected. Then, GP5 (adjusted OR: 0.805), GP17 (adjusted OR: 1.305), G12n (adjusted OR: 1.271), Gal_1 (adjusted OR: 0.776) and Fuc (adjusted OR: 0.737) were validated and significantly associated with esophageal precancerosis. In addition, there was a consistent positive association in GP17 and G12n and a negative association in GP5, Gal_1, and Fuc by restricted cubic spline function. Compared with esophageal inflammation, GP17, G12n, and Fuc were still independently associated with precancerosis. In brief, the IgG glycosylation profile was independently associated with esophageal precancerosis beyond inflammation, which could be an early biomarker for esophageal cancer.Prevention Relevance: IgG glycosylation profile is associated with esophageal precancerosis and specific IgG glycans involves in the early stage of esophageal cancer, which is independent of inflammation.
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Biomarcadores/análisis , Neoplasias Esofágicas/patología , Carcinoma de Células Escamosas de Esófago/patología , Inmunoglobulina G/metabolismo , Inflamación/patología , Polisacáridos/análisis , Lesiones Precancerosas/patología , Adulto , Anciano , Estudios de Casos y Controles , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/metabolismo , Carcinoma de Células Escamosas de Esófago/inmunología , Carcinoma de Células Escamosas de Esófago/metabolismo , Femenino , Glicosilación , Humanos , Inmunoglobulina G/análisis , Inflamación/inmunología , Inflamación/metabolismo , Masculino , Persona de Mediana Edad , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/metabolismoRESUMEN
BACKGROUND & AIMS: The association between cellular senescence and Helicobacter pylori-induced atrophic gastritis is not clear. Here, we explore the role of cellular senescence in H pylori-induced atrophic gastritis and the underlying mechanism. METHODS: C57BL/6J mice were infected with H pylori for biological and mechanistic studies in vivo. Gastric precancerous lesions from patients and mouse models were collected and analyzed using senescence-associated beta-galactosidase, Sudan Black B, and immunohistochemical staining to analyze senescent cells, signaling pathways, and H pylori infection. Chromatin immunoprecipitation, luciferase reporter assays, and other techniques were used to explore the underlying mechanism in vitro. RESULTS: Gastric mucosa atrophy was highly associated with cellular senescence. H pylori promoted gastric epithelial cell senescence in vitro and in vivo in a manner that depended on C-X-C motif chemokine receptor 2 (CXCR2) signaling. Interestingly, H pylori infection not only up-regulated the expression of CXCR2 ligands, C-X-C motif chemokine ligands 1 and 8, but also transcriptionally up-regulated the expression of CXCR2 via the nuclear factor-κB subunit 1 directly. In addition, CXCR2 formed a positive feedback loop with p53 to continually enhance senescence. Pharmaceutical inhibition of CXCR2 in an H pylori-infected mouse model attenuated mucosal senescence and atrophy, and delayed further precancerous lesion progression. CONCLUSIONS: Our study showed a new mechanism of H pylori-induced atrophic gastritis through CXCR2-mediated cellular senescence. Inhibition of CXCR2 signaling is suggested as a potential preventive therapy for targeting H pylori-induced atrophic gastritis. GEO data set accession numbers: GSE47797 and GSE3556.
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Senescencia Celular/inmunología , Gastritis Atrófica/inmunología , Infecciones por Helicobacter/inmunología , Lesiones Precancerosas/inmunología , Receptores de Interleucina-8B/metabolismo , Animales , Línea Celular , Senescencia Celular/efectos de los fármacos , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Femenino , Mucosa Gástrica/inmunología , Mucosa Gástrica/microbiología , Mucosa Gástrica/patología , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Gastritis Atrófica/prevención & control , Perfilación de la Expresión Génica , Técnicas de Silenciamiento del Gen , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Ratones , Ratones Endogámicos C57BL , Compuestos de Fenilurea/farmacología , Compuestos de Fenilurea/uso terapéutico , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Lesiones Precancerosas/prevención & control , Receptores de Interleucina-8B/antagonistas & inhibidores , Receptores de Interleucina-8B/genética , Transducción de Señal/inmunologíaRESUMEN
BACKGROUND & AIMS: Inflammation in the gastrointestinal tract may lead to the development of cancer. Dicarbonyl electrophiles, such as isolevuglandins (isoLGs), are generated from lipid peroxidation during the inflammatory response and form covalent adducts with amine-containing macromolecules. Thus, we sought to determine the role of dicarbonyl electrophiles in inflammation-associated carcinogenesis. METHODS: The formation of isoLG adducts was analyzed in the gastric tissues of patients infected with Helicobacter pylori from gastritis to precancerous intestinal metaplasia, in human gastric organoids, and in patients with colitis and colitis-associated carcinoma (CAC). The effect on cancer development of a potent scavenger of dicarbonyl electrophiles, 5-ethyl-2-hydroxybenzylamine (EtHOBA), was determined in transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils as models of H pylori-induced carcinogenesis and in C57BL/6 mice treated with azoxymethane-dextran sulfate sodium as a model of CAC. The effect of EtHOBA on mutations in gastric epithelial cells of H pylori-infected INS-GAS mice was assessed by whole-exome sequencing. RESULTS: We show increased isoLG adducts in gastric epithelial cell nuclei in patients with gastritis and intestinal metaplasia and in human gastric organoids infected with H pylori. EtHOBA inhibited gastric carcinoma in infected INS-GAS mice and gerbils and attenuated isoLG adducts, DNA damage, and somatic mutation frequency. Additionally, isoLG adducts were elevated in tissues from patients with colitis, colitis-associated dysplasia, and CAC as well as in dysplastic tumors of C57BL/6 mice treated with azoxymethane-dextran sulfate sodium. In this model, EtHOBA significantly reduced adduct formation, tumorigenesis, and dysplasia severity. CONCLUSIONS: Dicarbonyl electrophiles represent a link between inflammation and somatic genomic alterations and are thus key targets for cancer chemoprevention.
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Transformación Celular Neoplásica/inmunología , Neoplasias Asociadas a Colitis/inmunología , Lípidos/inmunología , Lesiones Precancerosas/inmunología , Neoplasias Gástricas/inmunología , Animales , Bencilaminas/farmacología , Bencilaminas/uso terapéutico , Núcleo Celular/metabolismo , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Asociadas a Colitis/microbiología , Neoplasias Asociadas a Colitis/patología , Neoplasias Asociadas a Colitis/prevención & control , Modelos Animales de Enfermedad , Células Epiteliales , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Mucosa Gástrica/patología , Gastritis/inmunología , Gastritis/microbiología , Gastritis/patología , Gerbillinae , Infecciones por Helicobacter/inmunología , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Helicobacter pylori/aislamiento & purificación , Humanos , Lípidos/antagonistas & inhibidores , Metaplasia/inmunología , Metaplasia/microbiología , Metaplasia/patología , Ratones , Ratones Transgénicos , Organoides , Lesiones Precancerosas/tratamiento farmacológico , Lesiones Precancerosas/microbiología , Lesiones Precancerosas/patología , Neoplasias Gástricas/microbiología , Neoplasias Gástricas/patología , Neoplasias Gástricas/prevención & controlRESUMEN
BACKGROUND & AIMS: Chronic atrophic gastritis can lead to gastric metaplasia and increase risk of gastric adenocarcinoma. Metaplasia is a precancerous lesion associated with an increased risk for carcinogenesis, but the mechanism(s) by which inflammation induces metaplasia are poorly understood. We investigated transcriptional programs in mucous neck cells and chief cells as they progress to metaplasia mice with chronic gastritis. METHODS: We analyzed previously generated single-cell RNA-sequencing (scRNA-seq) data of gastric corpus epithelium to define transcriptomes of individual epithelial cells from healthy BALB/c mice (controls) and TxA23 mice, which have chronically inflamed stomachs with metaplasia. Chronic gastritis was induced in B6 mice by Helicobacter pylori infection. Gastric tissues from mice and human patients were analyzed by immunofluorescence to verify findings at the protein level. Pseudotime trajectory analysis of scRNA-seq data was used to predict differentiation of normal gastric epithelium to metaplastic epithelium in chronically inflamed stomachs. RESULTS: Analyses of gastric epithelial transcriptomes revealed that gastrokine 3 (Gkn3) mRNA is a specific marker of mouse gastric corpus metaplasia (spasmolytic polypeptide expressing metaplasia, SPEM). Gkn3 mRNA was undetectable in healthy gastric corpus; its expression in chronically inflamed stomachs (from TxA23 mice and mice with Helicobacter pylori infection) identified more metaplastic cells throughout the corpus than previously recognized. Staining of healthy and diseased human gastric tissue samples paralleled these results. Although mucous neck cells and chief cells from healthy stomachs each had distinct transcriptomes, in chronically inflamed stomachs, these cells had distinct transcription patterns that converged upon a pre-metaplastic pattern, which lacked the metaplasia-associated transcripts. Finally, pseudotime trajectory analysis confirmed the convergence of mucous neck cells and chief cells into a pre-metaplastic phenotype that ultimately progressed to metaplasia. CONCLUSIONS: In analyses of tissues from chronically inflamed stomachs of mice and humans, we expanded the definition of gastric metaplasia to include Gkn3 mRNA and GKN3-positive cells in the corpus, allowing a more accurate assessment of SPEM. Under conditions of chronic inflammation, chief cells and mucous neck cells are plastic and converge into a pre-metaplastic cell type that progresses to metaplasia.
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Células Principales Gástricas/patología , Gastritis Atrófica/inmunología , Infecciones por Helicobacter/inmunología , Lesiones Precancerosas/diagnóstico , Neoplasias Gástricas/prevención & control , Animales , Biomarcadores/análisis , Biomarcadores/metabolismo , Carcinogénesis/genética , Carcinogénesis/inmunología , Proteínas Portadoras/análisis , Proteínas Portadoras/metabolismo , Células Principales Gástricas/inmunología , Modelos Animales de Enfermedad , Femenino , Gastritis Atrófica/microbiología , Gastritis Atrófica/patología , Infecciones por Helicobacter/genética , Infecciones por Helicobacter/microbiología , Infecciones por Helicobacter/patología , Helicobacter pylori/inmunología , Humanos , Masculino , Proteínas de la Membrana/análisis , Proteínas de la Membrana/metabolismo , Metaplasia/diagnóstico , Metaplasia/genética , Metaplasia/inmunología , Metaplasia/patología , Ratones , Lesiones Precancerosas/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , RNA-Seq , Análisis de la Célula Individual , Neoplasias Gástricas/patologíaRESUMEN
BACKGROUND & AIMS: The association between chronic inflammation and gastric carcinogenesis is well established, but it is not clear how immune cells and cytokines regulate this process. We investigated the role of interleukin 27 (IL27) in the development of gastric atrophy, hyperplasia, and metaplasia (preneoplastic lesions associated with inflammation-induced gastric cancer) in mice with autoimmune gastritis. METHODS: We performed studies with TxA23 mice (control mice), which express a T-cell receptor against the H+/K+ adenosine triphosphatase α chain and develop autoimmune gastritis, and TxA23xEbi3-/- mice, which develop gastritis but do not express IL27. In some experiments, mice were given high-dose tamoxifen to induce parietal cell atrophy and spasmolytic polypeptide-expressing metaplasia (SPEM). Recombinant IL27 was administered to mice with mini osmotic pumps. Stomachs were collected and analyzed by histopathology and immunofluorescence; we used flow cytometry to measure IL27 and identify immune cells that secrete IL27 in the gastric mucosa. Single-cell RNA sequencing was performed on immune cells that infiltrated stomach tissues. RESULTS: We identified IL27-secreting macrophages and dendritic cell in the corpus of mice with chronic gastritis (TxA23 mice). Mice deficient in IL27 developed more severe gastritis, atrophy, and SPEM than control mice. Administration of recombinant IL27 significantly reduced the severity of inflammation, atrophy, and SPEM in mice with gastritis. Single-cell RNA sequencing showed that IL27 acted almost exclusively on stomach-infiltrating CD4+ T cells to suppress expression of inflammatory genes. CONCLUSIONS: In studies of mice with autoimmune gastritis, we found that IL27 is an inhibitor of gastritis and SPEM, suppressing CD4+ T-cell-mediated inflammation in the gastric mucosa.
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Enfermedades Autoinmunes/tratamiento farmacológico , Mucosa Gástrica/patología , Gastritis/tratamiento farmacológico , Interleucinas/administración & dosificación , Lesiones Precancerosas/prevención & control , Animales , Atrofia/inmunología , Atrofia/patología , Atrofia/prevención & control , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Enfermedad Crónica/tratamiento farmacológico , Modelos Animales de Enfermedad , Femenino , Mucosa Gástrica/citología , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/inmunología , Gastritis/diagnóstico , Gastritis/inmunología , Gastritis/patología , Humanos , Masculino , Metaplasia/inmunología , Metaplasia/patología , Metaplasia/prevención & control , Ratones , Ratones Noqueados , Antígenos de Histocompatibilidad Menor/genética , Lesiones Precancerosas/inmunología , Lesiones Precancerosas/patología , Receptores de Citocinas/genética , Proteínas Recombinantes/administración & dosificación , Índice de Severidad de la EnfermedadRESUMEN
The interactome - the network of protein-protein interactions (PPIs) within a cell or organism - is technically difficult to assess. Bioinformatic tools can, not only, identify potential PPIs that can be later experimentally validated, but also be used to assign functional meaning to PPIs. Saliva's potential as a non-invasive diagnostic fluid is currently being explored by several research groups. But, in order to fully attain its potential, it is necessary to achieve the full characterization of the mechanisms that take place within this ecosystem. The onset of omics technologies, and specifically of proteomics, delivered a huge set of data that is largely underexplored. Quantitative information relative to proteins within a given context (for example a given disease) can be used by computational algorithms to generate information regarding PPIs. These PPIs can be further analyzed concerning their functional meaning and used to identify potential biomarkers, therapeutic targets, defense and pathogenicity mechanisms. We describe a computational pipeline that can be used to identify and analyze PPIs between human and microbial proteins. The pipeline was tested within the scenario of human PPIs of systemic (Zika Virus infection) and of oral conditions (Periodontal disease) and also in the context of microbial interactions (Candida-Streptococcus) and showed to successfully predict functionally relevant PPIs. The pipeline can be applied to different scientific areas, such as pharmacological research, since a functional meaningful PPI network can provide insights on potential drug targets, and even new uses for existing drugs on the market.