RESUMEN
Doublecortin-like kinase 1 (DCLK1), a significant constituent of the protein kinase superfamily and the doublecortin family, has been recognized as a prooncogenic factor that exhibits a strong association with the malignant progression and clinical prognosis of various cancers. DCLK1 serves as a stem cell marker that governs tumorigenesis, tumor cell reprogramming, and epithelial-mesenchymal transition. Multiple studies have indicated the capable of DCLK1 in regulating the DNA damage response and facilitating DNA damage repair. Additionally, DCLK1 is involved in the regulation of the immune microenvironment and the promotion of tumor immune evasion. Recently, DCLK1 has emerged as a promising therapeutic target for a multitude of cancers. Several small-molecule inhibitors of DCLK1 have been identified. Nevertheless, the biological roles of DCLK1 are mainly ambiguous, particularly with the disparities between its α- and ß-form transcripts in the malignant progression of cancers, which impedes the development of more precisely targeted drugs. This article focuses on tumor stem cells, tumor epithelial-mesenchymal transition, the DNA damage response, and the tumor microenvironment to provide a comprehensive overview of the association between DCLK1 and tumor malignant progression, address unsolved questions and current challenges, and project future directions for targeting DCLK1 for the diagnosis and treatment of cancers.
Asunto(s)
Quinasas Similares a Doblecortina , Neoplasias , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/enzimología , Neoplasias/genética , Quinasas Similares a Doblecortina/antagonistas & inhibidores , Quinasas Similares a Doblecortina/genética , Quinasas Similares a Doblecortina/inmunología , Transición Epitelial-Mesenquimal/genética , Transición Epitelial-Mesenquimal/inmunología , Células Madre Neoplásicas , Reparación del ADN/genética , Reparación del ADN/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Escape del Tumor/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Humanos , Isoformas de ProteínasRESUMEN
Radiation is an essential preparative procedure for bone marrow (BM) transplantation and cancer treatment. The therapeutic efficacy of radiation and associated toxicity varies from patient to patient, making it difficult to prescribe an optimal patient-specific irradiation dose. The molecular determinants of radiation response remain unclear. AIM2-like receptors (ALRs) are key players in innate immunity and determine the course of infections, inflammatory diseases, senescence, and cancer. Here it is reported that mice lacking ALRs are resistant to irradiation-induced BM injury. It is shown that nuclear ALRs are inhibitors of DNA repair, thereby accelerate genome destabilization, micronuclei generation, and cell death, and that this novel function is uncoupled from their role in innate immunity. Mechanistically, ALRs bind to and interfere with chromatin decompaction vital for DNA repair. The finding uncovers ALRs as targets for new interventions against genotoxic tissue injury and as possible biomarkers for predicting the outcome of radio/chemotherapy.
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Muerte Celular/genética , Daño del ADN/genética , Reparación del ADN/genética , Proteínas de Unión al ADN/genética , Animales , Muerte Celular/inmunología , Reparación del ADN/inmunología , Proteínas de Unión al ADN/inmunología , Modelos Animales de Enfermedad , Inmunidad Innata/genética , Inmunidad Innata/inmunología , Ratones , Transducción de Señal/genética , Transducción de Señal/inmunologíaRESUMEN
Tumors with DNA damage repair (DDR) deficiency accumulate genomic alterations that may serve as neoantigens and increase sensitivity to immune checkpoint inhibitor. However, over half of DDR-deficient tumors are refractory to immunotherapy, and it remains unclear which mutations may promote immunogenicity in which cancer types. We integrate deleterious somatic and germline mutations and methylation data of DDR genes in 10,080 cancers representing 32 cancer types and evaluate the associations of these alterations with tumor neoantigens and immune infiltrates. Our analyses identify DDR pathway mutations that are associated with higher neoantigen loads, adaptive immune markers, and survival outcomes of immune checkpoint inhibitor-treated animal models and patients. Different immune phenotypes are associated with distinct types of DDR deficiency, depending on the cancer type context. The comprehensive catalog of immune response-associated DDR deficiency may explain variations in immunotherapy outcomes across DDR-deficient cancers and facilitate the development of genomic biomarkers for immunotherapy.
Asunto(s)
Biomarcadores de Tumor/inmunología , Daño del ADN/inmunología , Trastornos por Deficiencias en la Reparación del ADN/inmunología , Reparación del ADN/inmunología , Neoplasias/genética , Biomarcadores de Tumor/genética , Daño del ADN/genética , Reparación del ADN/genética , Trastornos por Deficiencias en la Reparación del ADN/genética , Genómica/métodos , Humanos , Inmunidad/genética , Inmunoterapia/métodos , Mutación/genéticaRESUMEN
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
Asunto(s)
Envejecimiento/inmunología , Envejecimiento/fisiología , Sistema Inmunológico/inmunología , Sistema Inmunológico/fisiología , Inmunosenescencia/inmunología , Inmunosenescencia/fisiología , Especificidad de Órganos/inmunología , Especificidad de Órganos/fisiología , Envejecimiento/efectos de los fármacos , Envejecimiento/patología , Animales , Daño del ADN/inmunología , Daño del ADN/fisiología , Reparación del ADN/inmunología , Reparación del ADN/fisiología , Proteínas de Unión al ADN/genética , Endonucleasas/genética , Femenino , Envejecimiento Saludable/inmunología , Envejecimiento Saludable/fisiología , Homeostasis/inmunología , Homeostasis/fisiología , Sistema Inmunológico/efectos de los fármacos , Inmunosenescencia/efectos de los fármacos , Masculino , Ratones , Especificidad de Órganos/efectos de los fármacos , Rejuvenecimiento , Sirolimus/farmacología , Bazo/citología , Bazo/trasplanteRESUMEN
Interferon-gamma (IFN-γ) plays a complex role in modulating tumor microenvironment during lung adenocarcinoma (LUAD) development. In order to define the role of IFN-γ response genes in LUAD progression, we characterized the gene expression, mutation profile, protein-protein interaction of 24 IFN-γ response genes, which exhibited significant hazard ratio in overall survival. Two subgroups of LUAD from the TCGA cohort, which showed significant difference in the survival rate, were identified based on the expression of these genes. Furthermore, LASSO penalized cox regression model was used to derive a risk signature comprising seven IFN-γ response genes, including CD74, CSF2RB, PTPN6, MT2A, NMI, LATS2, and PFKP, which can serve as an independent prognostic predictor of LUAD. The risk signature was validated in an independent LUAD cohort. The high risk group is enriched with genes regulating cell cycle and DNA replication, as well as a high level of pro-tumor immune cells. In addition, the risk score is negatively correlated with the expression of immune metagenes, but positively correlated with DNA damage repair genes. Our findings reveal that seven-gene risk signature can be a valuable prognostic predictor for LUAD, and they are crucial participants in tumor microenvironment of LUAD.
Asunto(s)
Adenocarcinoma del Pulmón/mortalidad , Biomarcadores de Tumor/genética , Interferón gamma/metabolismo , Neoplasias Pulmonares/mortalidad , Microambiente Tumoral/inmunología , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Biología Computacional , Reparación del ADN/inmunología , Conjuntos de Datos como Asunto , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Estimación de Kaplan-Meier , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Pronóstico , Medición de Riesgo/métodos , Transducción de Señal/genética , Transducción de Señal/inmunología , Tasa de Supervivencia , Transcriptoma/inmunologíaRESUMEN
BACKGROUND: Genetic alterations have been proven to be the promising biomarkers for ICI response. However, sex biases in genetic alterations have been often ignored in the field of immunotherapy, which might specially influence the anticancer immunity and immunotherapy efficacy in male or female patients. Here, we have systematically evaluated the effect of the sex biases in somatic mutation of gastric cancer (GC) patients on the anticancer immunity and clinical benefit to immunotherapy. METHODS: Genomic and transcriptomic data of gastric cancer were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC). We also obtained the genomic and clinical data of a MSKCC ICI-treated cohort from cbioportal database. GC male and female-derived tumor somatic mutation profiles were compared by maftools R package. Single sample gene set enrichment analysis (ssGSEA) was conducted to calculate the score of the anticancer immunity indicators including IFN-γ signaling, cytolytic activity (CYT) and antigen presenting machinery (APM). RESULTS: ATRX was found to mutate more frequently in female GC patients compared to male patients (FDR = 0.0108). Female GC patients with ATRX mutation manifested significantly more MSI-high subtypes, increased TMB and PDL1 expression as well as higher scores of IFN-γ signaling, CYT and APM. Gene set enrichment analysis (GSEA) has shown that ATRX mutation might enhance the immunogenicity and anticancer immunity through affecting DNA damage repair pathways. In the ICI-treated cohort from MSKCC, GC patients with ATRX mutation were associated with prolonged overall survival. When stratifying the entire ICI-treated cohort by sex, female patients with ATRX mutation obtained significantly better survival benefits than that of ATRX mutant male patients (Female patients, HR of ATRX MT vs WT = 0.636, 95%CI = 0.455-0.890, P = 0.023; Male patients, HR of ATRX MT vs WT = 0.929, 95%CI = 0.596-1.362, P = 0.712). CONCLUSIONS: ATRX mutation might serve as a potential predictive biomarker for favorable clinical benefit to ICI in female GC patients. ATRX mutation could be applied in combination with other biomarkers of ICI response to better identify the female GC patients who will derive greater benefits from ICI therapy.
Asunto(s)
Biomarcadores de Tumor/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Proteína Nuclear Ligada al Cromosoma X/genética , Anciano , Biopsia , Análisis Mutacional de ADN , Reparación del ADN/inmunología , Conjuntos de Datos como Asunto , Resistencia a Antineoplásicos/genética , Resistencia a Antineoplásicos/inmunología , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Estimación de Kaplan-Meier , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Inestabilidad de Microsatélites , Persona de Mediana Edad , Mutación , RNA-Seq , Factores Sexuales , Estómago/inmunología , Estómago/patología , Neoplasias Gástricas/genética , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/mortalidadRESUMEN
Aging is associated with DNA accumulation and increased homeostatic proliferation of circulating T cells. Although these attributes are associated with aging-related autoimmunity, their direct contributions remain unclear. Conventionally, KU complex, the regulatory subunit of DNA-dependent protein kinase (DNA-PK), together with the catalytic subunit of DNA-PK (DNA-PKcs), mediates DNA damage repair in the nucleus. Here, we found KU complex abundantly expressed in the cytoplasm, where it recognized accumulated cytoplasmic DNA in aged human and mouse CD4+ T cells. This process enhanced T cell activation and pathology of experimental autoimmune encephalomyelitis (EAE) in aged mice. Mechanistically, KU-mediated DNA sensing facilitated DNA-PKcs recruitment and phosphorylation of the kinase ZAK. This activated AKT and mTOR pathways, promoting CD4+ T cell proliferation and activation. We developed a specific ZAK inhibitor, which dampened EAE pathology in aged mice. Overall, these findings demonstrate a KU-mediated cytoplasmic DNA-sensing pathway in CD4+ T cells that potentiates aging-related autoimmunity.
Asunto(s)
Envejecimiento/inmunología , Enfermedades Autoinmunes/inmunología , Linfocitos T CD4-Positivos/inmunología , Citoplasma/inmunología , Proteína Quinasa Activada por ADN/inmunología , ADN/inmunología , Inflamación/inmunología , Animales , Línea Celular , Línea Celular Tumoral , Núcleo Celular/inmunología , Proliferación Celular/fisiología , Reparación del ADN/inmunología , Células HEK293 , Humanos , Células Jurkat , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Células U937RESUMEN
The aim of this study was to identify the key similarities between the eutopic endometrium of women with endometriosis and chlamydia-induced endometritis taking into account tissue microenvironment heterogeneity, transcript gene profile, and enriched pathways. A meta-analysis of whole transcriptome microarrays was performed using publicly available data, including samples containing both glandular and stromal endometrial components. Control samples were obtained from women without any reported pathological condition. Only samples obtained during the proliferative menstrual phase were included. Cellular tissue heterogeneity was predicted using a method that integrates gene set enrichment and deconvolution approaches. The batch effect was estimated by principal variant component analysis and removed using an empirical Bayes method. Differentially expressed genes were identified using an adjusted p-value < 0.05 and fold change = 1.5. The protein-protein interaction network was built using the STRING database and interaction score over 400. The Molecular Signatures Database was used to analyse the functional enrichment analysis. Both conditions showed similarities in cell types in the microenvironment, particularly CD4+ and CD8+ Tem cells, NKT cells, Th2 cells, basophils, and eosinophils. With regards to the regulation of cellular senescence and DNA integrity/damage checkpoint, which are commonly enriched pathways, 21 genes were down-regulated and directly related to DNA repair. Compared to the endometriosis samples, some chlamydial endometritis samples presented a lack of enriched immune pathways. Our results suggest that both conditions show similar distributions of microenvironment cell types, the downregulation of genes involved in DNA repair and cell cycle control, and pathways involved in immune response evasion.
Asunto(s)
Infecciones por Chlamydia/inmunología , Endometriosis/inmunología , Endometritis/inmunología , Evasión Inmune/genética , Chlamydia/inmunología , Infecciones por Chlamydia/complicaciones , Infecciones por Chlamydia/genética , Infecciones por Chlamydia/microbiología , Reparación del ADN/inmunología , Conjuntos de Datos como Asunto , Regulación hacia Abajo/inmunología , Endometriosis/genética , Endometriosis/patología , Endometritis/complicaciones , Endometritis/genética , Endometritis/microbiología , Endometrio/inmunología , Endometrio/microbiología , Endometrio/patología , Femenino , Perfilación de la Expresión Génica , HumanosRESUMEN
DNA damage repair (DDR) comprises the detection and correction of alterations in the chemical structure of DNA. The dysfunction of the DDR process has been determined to have important implications for tumor carcinogenesis, malignancy progression, treatment resistance, and prognosis assessment. However, the role of the DDR process in gastric cancer (GC) remains to be fully understood. Thus, a total of 2,019 GC samples from our hospital (Harbin Medical University Cancer Hospital in china) and 12 public data sets were included in our study. In this study, single-sample gene set enrichment analysis (ssGSEA) was used to generate the DDR pathway activity profiles of 8 DDR sub-pathways and identify a DDR pathway signature by combining the DDR sub-pathway gene sets. The DDR pathway profiling's impacts on the clinical outcomes, biological functions, genetic variants, immune heterogeneity, and treatment responses were analyzed through multidimensional genomics and clinical data. The results demonstrate that the DDR pathway profiling was clearly distinguished between tumor and normal tissues. The DDR pathway profiling reveals patient-level variations, which may contribute to explaining the high heterogeneity of human GC for the biological features and treatment outcomes. Thus, tumors with low DDR signature scores were independently correlated with shorter overall survival time and significantly associated with mesenchymal, invasion, and metastasis phenotypes. The statistical model integrating this DDR pathway signature with other clinical predictors outperforms each predictor alone for predicting overall survival in discrimination, calibration, and net clinical benefit. Moreover, low DDR signature scores were tightly associated with genome stability, characterized by low tumor mutational burden (TMB) and low fractions of genome alteration. Furthermore, this study confirms that patients with low DDR pathway signature scores might not benefit from adjuvant chemotherapy and a monoclonal antibody directed against programmed cell death-1 ligand 1 (anti-PD1) therapy. These findings highlighted that the DDR pathway profiling confers important implications for patients with GC and provides insights into the specific clinical and molecular features underlying the DDR process, which may help to facilitate clinical management.
Asunto(s)
Daño del ADN/inmunología , Reparación del ADN/inmunología , Transducción de Señal/inmunología , Neoplasias Gástricas/inmunología , Transcriptoma/inmunología , Anciano , Antineoplásicos/uso terapéutico , Reparación del ADN/genética , Femenino , Perfilación de la Expresión Génica/métodos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Pronóstico , Transducción de Señal/genética , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Análisis de Supervivencia , Transcriptoma/genéticaRESUMEN
High-risk Human Papillomavirus (HPV) infections have recently emerged as an independent risk factor in head and neck squamous cell carcinoma (HNSCC). There has been a marked increase in the incidence of HPV-induced HNSCC subtype, which demonstrates different genetics with better treatment outcome. Despite the favourable prognosis of HPV-HNSCC, the treatment modality, consisting of high dose radiotherapy (RT) in combination with chemotherapy (CT), remains similar to HPV-negative tumours, associated with toxic side effects. Epidermal growth factor receptor (EGFR) is overexpressed in over 80% of HNSCC and correlates with RT resistance. EGFR inhibitor Cetuximab is the only FDA approved targeted therapy for both HNSCC subtypes, however the response varies between HNSCC subtypes. In HPV-negative HNSCC, Cetuximab sensitises HNSCC to RT improving survival rates. To reduce adverse cytotoxicity of CT, Cetuximab has been approved for treatment de-escalation of HPV-positive HNSCC. The results of several recent clinical trials have concluded differing outcome to HPV-negative HNSCC. Here we investigated the role of EGFR in HPV-positive HNSCC response to RT. Remarkably, in HPV-positive HNSCC cell lines and in vivo tumour models, EGFR activation was strongly indicative of increased RT response. In response to RT, EGFR activation induced impairment of DNA damage repair and increased RT response. Furthermore, EGFR was found to downregulate HPV oncoproteinE6 expression and induced p53 activity in response to RT. Collectively, our data uncovers a novel role for EGFR in virally induced HNSCC and highlights the importance of using EGFR-targeted therapies in the context of the genetic makeup of cancer.
Asunto(s)
Daño del ADN/genética , Reparación del ADN/inmunología , Neoplasias de Cabeza y Cuello/genética , Proteínas Oncogénicas Virales/genética , Infecciones por Papillomavirus/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/virología , Animales , Línea Celular , Línea Celular Tumoral , Cetuximab/farmacología , Reparación del ADN/efectos de los fármacos , Reparación del ADN/genética , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/genética , Receptores ErbB/genética , Células HEK293 , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Neoplasias de Cabeza y Cuello/virología , Humanos , Ratones , Ratones Endogámicos NOD , Infecciones por Papillomavirus/virología , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapiaRESUMEN
Significance: Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased tendency to accrue DNA damage, chromosomal instability, or aberrant DNA localization. Apart from the cell autonomous tumor-promoting effects, genomic stress in cancer cells could have a profound impact on the tumor microenvironment. Recent Advances: Recently, it is increasingly appreciated that harnessing genomic stress could provide a promising strategy to revive antitumor immunity, and thereby offer new therapeutic opportunities in cancer treatment. Critical Issues: Genomic stress is closely intertwined with antitumor immunity via mechanisms involving the direct crosstalk with DNA damage response components, upregulation of immune-stimulatory/inhibitory ligands, release of damage-associated molecular patterns, increase of neoantigen repertoire, and activation of DNA sensing pathways. A better understanding of these mechanisms will provide molecular basis for exploiting the genomic stress to boost antitumor immunity. Future Directions: Future research should pay attention to the heterogeneity between individual cancers in the genomic instability and the associated immune response, and how to balance the toxicity and benefit by specifying the types, potency, and treatment sequence of genomic stress inducer in therapeutic practice. Antioxid. Redox Signal. 34, 1128-1150.
Asunto(s)
Inestabilidad Genómica , Genómica , Inmunidad Innata/genética , Neoplasias/genética , Daño del ADN/genética , Daño del ADN/inmunología , Reparación del ADN/genética , Reparación del ADN/inmunología , Genoma Humano/genética , Genoma Humano/inmunología , Humanos , Neoplasias/inmunología , Neoplasias/metabolismo , Neoplasias/patología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Recently, great advancements have been made towards understanding the mechanisms underlying dermatomyositis (DM). Many novel autoantibodies, such as anti-MDA5, anti-TIF1γ, anti-NXP2, and anti-SAE, have been reported to be involved in DM. DM is now classified based on these myositis-specific autoantibodies. Anti-TIF1γ antibodies are closely associated with juvenile DM and adult cancer-associated DM. Anti-TIF1γ antibody-positive DM tends to present severe cutaneous manifestations, mild myositis, and dysphagia. TIF1γ (also known as TRIM33) plays a role in transcriptional elongation, DNA repair, differentiation of cells, embryonic development, and mitosis. Moreover, TIF1γ has been shown to suppress various tumors via the TGF-ß/Smad and the Wnt/ß-Catenin signaling pathways. In this review, we explore the relationship between TIF1γ, cancer, and DM. We also discuss the pathogenesis of anti-TIF1γ antibody-positive DM.
Asunto(s)
Autoanticuerpos , Dermatomiositis/inmunología , Proteínas Nucleares/inmunología , Factores de Transcripción/inmunología , Reparación del ADN/inmunología , Desarrollo Embrionario/inmunología , Humanos , Mitosis/inmunología , Elongación de la Transcripción Genética/inmunología , Factores de Transcripción/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Vía de Señalización Wnt/inmunologíaRESUMEN
Memory T cells respond rapidly in part because they are less reliant on a heightened levels of costimulatory molecules. This enables rapid control of secondary infecting pathogens but presents challenges to efforts to control or silence memory CD4 T cells, for example in antigen-specific tolerance strategies for autoimmunity. We have examined the transcriptional and functional consequences of reactivating memory CD4 T cells in the absence of an adjuvant. We find that memory CD4 T cells generated by infection or immunisation survive secondary activation with antigen delivered without adjuvant, regardless of their location in secondary lymphoid organs or peripheral tissues. These cells were, however, functionally altered following a tertiary immunisation with antigen and adjuvant, proliferating poorly but maintaining their ability to produce inflammatory cytokines. Transcriptional and cell cycle analysis of these memory CD4 T cells suggests they are unable to commit fully to cell division potentially because of low expression of DNA repair enzymes. In contrast, these memory CD4 T cells could proliferate following tertiary reactivation by viral re-infection. These data indicate that antigen-specific tolerogenic strategies must examine multiple parameters of Tcell function, and provide insight into the molecular mechanisms that may lead to deletional tolerance of memory CD4 T cells.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Tolerancia Inmunológica/inmunología , Memoria Inmunológica/inmunología , Animales , Antígenos/inmunología , Autoinmunidad/inmunología , Ciclo Celular/inmunología , Proliferación Celular/fisiología , Citocinas/inmunología , Reparación del ADN/inmunología , Femenino , Inflamación/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Transcripción Genética/inmunologíaRESUMEN
Cancer-associated fibroblasts (CAF) form the basis of tumor microenvironment and possess immunomodulatory functions by interacting with other cells surrounding tumor, including T lymphocytes, macrophages, dendritic cells and natural killer cells. Ionizing radiation is a broadly-used method in radiotherapy to target tumors. In mammalian cells, ionizing radiation induces various types of DNA damages and DNA damage response. Being unspecific, radiotherapy affects all the cells in tumor microenvironment, including the tumor itself, CAFs and immune cells. CAFs are extremely radio-resistant and do not initiate apoptosis even at high doses of radiation. However, following radiation, CAFs become senescent and produce a distinct combination of immunoregulatory molecules. Radiosensitivity of immune cells varies depending on the cell type due to inefficient DNA repair in, for example, monocytes and granulocytes. In this minireview, we are summarizing recent findings on the interaction between CAF, ionizing radiation and immune cells in the tumor microenvironment.
Asunto(s)
Fibroblastos Asociados al Cáncer , Granulocitos , Monocitos , Neoplasias , Radiación Ionizante , Linfocitos T , Microambiente Tumoral , Animales , Fibroblastos Asociados al Cáncer/inmunología , Fibroblastos Asociados al Cáncer/patología , Daño del ADN/inmunología , Reparación del ADN/inmunología , Reparación del ADN/efectos de la radiación , Granulocitos/inmunología , Granulocitos/patología , Humanos , Monocitos/inmunología , Monocitos/patología , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/radioterapia , Linfocitos T/inmunología , Linfocitos T/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiaciónRESUMEN
Congenital defects of the immune system called primary immunodeficiency disorders (PID) describe a group of diseases characterized by a decrease, an absence, or a malfunction of at least one part of the immune system. As a result, PID patients are more prone to develop life-threatening complications, including cancer. PID currently include over 400 different disorders, however, the variety of PID-related cancers is narrow. We discuss here reasons for this clinical phenotype. Namely, PID can lead to cell intrinsic failure to control cell transformation, failure to activate tumor surveillance by cytotoxic cells or both. As the most frequent tumors seen among PID patients stem from faulty lymphocyte development leading to leukemia and lymphoma, we focus on the extensive genomic alterations needed to create the vast diversity of B and T lymphocytes with potential to recognize any pathogen and why defects in these processes lead to malignancies in the immunodeficient environment of PID patients. In the second part of the review, we discuss PID affecting tumor surveillance and especially membrane trafficking defects caused by altered exocytosis and regulation of the actin cytoskeleton. As an impairment of these membrane trafficking pathways often results in dysfunctional effector immune cells, tumor cell immune evasion is elevated in PID. By considering new anti-cancer treatment concepts, such as transfer of genetically engineered immune cells, restoration of anti-tumor immunity in PID patients could be an approach to complement standard therapies.
Asunto(s)
Leucemia de Células B/etiología , Linfoma de Células B/etiología , Enfermedades de Inmunodeficiencia Primaria/complicaciones , Citoesqueleto de Actina/genética , Citoesqueleto de Actina/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Proliferación Celular , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Reparación del ADN/genética , Reparación del ADN/inmunología , Exocitosis/genética , Exocitosis/inmunología , Inestabilidad Genómica , Humanos , Sinapsis Inmunológicas/genética , Leucemia de Células B/genética , Leucemia de Células B/inmunología , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Modelos Inmunológicos , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Factores de Riesgo , Escape del Tumor/genéticaRESUMEN
BACKGROUND: ARID1A is a key subunit of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex which regulates dynamic repositioning of nucleosomes to repair DNA damage. Only small pilot studies have evaluated the role of ARID1A mutation in colorectal cancer (CRC). The aim of the present study was to explore the potential impact of ARID1A mutation on clinicopathological and molecular characteristics in CRC. METHODS: We used integrated data sets of 7978 CRC cases (one data set from a clinical laboratory improvement amendments [CLIA]-certified laboratory and three independent published data sets). The associations of ARID1A mutation with molecular characteristics including immune profile (the status of microsatellite instability [MSI], tumour mutational burden [TMB], programmed death ligand 1 [PD-L1] and estimated infiltrating immune cells), clinicopathological features and related pathways were analysed using next-generation sequencing, RNA sequencing and immunohistochemistry. RESULTS: ARID1A mutant samples had more genomically unstable tumour features (MSI-high and TMB-high) and exhibited more characteristics of a T-cell-inflamed microenvironment (PD-L1 expression and high estimated infiltrating cytotoxic T lymphocytes [CTLs]) than ARID1A wild-type samples in the discovery and validation cohorts. Even ARID1A mutant samples without MSI-high status were TMB-high, had high levels of PD-L1 expression and high estimated infiltrating CTLs. ARID1A mutations were more common with right-sided primary and earlier stage tumours. ARID1A mutant tumours mainly had co-occurring gene mutations related to chromatin modifying, DNA repair, WNT signalling and epidermal growth factor receptor inhibitor resistance pathways, and ARID1A mutations strongly regulated DNA repair pathways. Key genes for chemotherapy/radiotherapy sensitivity were suppressed in ARID1A mutant samples. CONCLUSIONS: Our findings may provide novel insights to develop individualised approaches for treatment of CRC based on ARID1A mutation status.
Asunto(s)
Neoplasias Colorrectales/genética , Proteínas de Unión al ADN/genética , Mutación/genética , Factores de Transcripción/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Colorrectales/inmunología , Reparación del ADN/genética , Reparación del ADN/inmunología , Proteínas de Unión al ADN/inmunología , Femenino , Humanos , Inmunohistoquímica/métodos , Masculino , Persona de Mediana Edad , Mutación/inmunología , Linfocitos T Citotóxicos/inmunología , Factores de Transcripción/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Adulto JovenRESUMEN
The purpose of the manuscript is to provide a step-by-step protocol for performing immunofluorescence microscopy to study the radiation-induced DNA damage response induced by neutron-gamma mixed-beam used in boron neutron capture therapy (BNCT). Specifically, the proposed methodology is applied for the detection of repair proteins activation which can be visualized as foci using antibodies specific to DNA double-strand breaks (DNA-DSBs). DNA repair foci were assessed by immunofluorescence in colon cancer cells (HCT-116) after irradiation with the neutron-mixed beam. DNA-DSBs are the most genotoxic lesions and are repaired in mammalian cells by two major pathways: non-homologous end-joining pathway (NHEJ) and homologous recombination repair (HRR). The frequencies of foci, immunochemically stained, for commonly used markers in radiobiology like γ-H2AX, 53BP1 are associated with DNA-DSB number and are considered as efficient and sensitive markers for monitoring the induction and repair of DNA-DSBs. It was established that γ-H2AX foci attract repair proteins, leading to a higher concentration of repair factors near a DSB. To monitor DNA damage at the cellular level, immunofluorescence analysis for the presence of DNA-PKcs representative repair protein foci from the NHEJ pathway and Rad52 from the HRR pathway was planned. We have developed and introduced a reliable immunofluorescence staining protocol for the detection of radiation-induced DNA damage response with antibodies specific for repair factors from NHEJ and HRR pathways and observed radiation-induced foci (RIF). The proposed methodology can be used for investigating repair protein that is highly activated in the case of neutron-mixed beam radiation, thereby indicating the dominance of the repair pathway.
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Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/genética , Daño del ADN/inmunología , Reparación del ADN/inmunología , Técnica del Anticuerpo Fluorescente/métodos , HumanosRESUMEN
Prostate cancer is a major cause of cancer morbidity and mortality. Intra-prostatic inflammation is a risk factor for prostate carcinogenesis, with diet, chemical injury and an altered microbiome being causally implicated. Intra-prostatic inflammatory cell recruitment and expansion can ultimately promote DNA double-strand breaks and androgen receptor activation in prostate epithelial cells. The activation of the senescence-associated secretory phenotype fuels further 'inflammatory storms', with free radicals leading to further DNA damage. This drives the overexpression of DNA repair and tumour suppressor genes, rendering these genes susceptible to mutagenic insults, with carcinogenesis accelerated by germline DNA repair gene defects. We provide updates on recent advances in elucidating prostate carcinogenesis and explore novel therapeutic and prevention strategies harnessing these discoveries.
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Carcinogénesis/inmunología , Inflamación/inmunología , Próstata/inmunología , Neoplasias de la Próstata/inmunología , Receptores Androgénicos/inmunología , Carcinogénesis/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/inmunología , Enfermedad Crónica , Roturas del ADN de Doble Cadena , Daño del ADN/genética , Daño del ADN/inmunología , Reparación del ADN/genética , Reparación del ADN/inmunología , Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Grasas de la Dieta/inmunología , Humanos , Inflamación/etiología , Inflamación/genética , Masculino , Microbiota/inmunología , Obesidad/complicaciones , Obesidad/inmunología , Comunicación Paracrina/inmunología , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/genética , Receptores Androgénicos/genética , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
The integrity of the genome is under constant threat of environmental and endogenous agents that cause DNA damage. Endogenous damage is particularly pervasive, occurring at an estimated rate of 10,000-30,000 per cell/per day, and mostly involves chemical DNA base lesions caused by oxidation, depurination, alkylation, and deamination. The base excision repair (BER) pathway is primary responsible for removing and repairing these small base lesions that would otherwise lead to mutations or DNA breaks during replication. Next to preventing DNA mutations and damage, the BER pathway is also involved in mutagenic processes in B cells during immunoglobulin (Ig) class switch recombination (CSR) and somatic hypermutation (SHM), which are instigated by uracil (U) lesions derived from activation-induced cytidine deaminase (AID) activity. BER is required for the processing of AID-induced lesions into DNA double strand breaks (DSB) that are required for CSR, and is of pivotal importance for determining the mutagenic outcome of uracil lesions during SHM. Although uracils are generally efficiently repaired by error-free BER, this process is surprisingly error-prone at the Ig loci in proliferating B cells. Breakdown of this high-fidelity process outside of the Ig loci has been linked to mutations observed in B-cell tumors and DNA breaks and chromosomal translocations in activated B cells. Next to its role in preventing cancer, BER has also been implicated in immune tolerance. Several defects in BER components have been associated with autoimmune diseases, and animal models have shown that BER defects can cause autoimmunity in a B-cell intrinsic and extrinsic fashion. In this review we discuss the contribution of BER to genomic integrity in the context of immune receptor diversification, cancer and autoimmune diseases.
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Linfocitos B/inmunología , Reparación del ADN/inmunología , ADN/genética , Animales , Roturas del ADN de Doble Cadena , Daño del ADN , Humanos , Sistema Inmunológico , Cambio de Clase de Inmunoglobulina , Hipermutación Somática de InmunoglobulinaRESUMEN
BACKGROUND: Loss-of-function alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may determine benefit from immune-oncology (I/O) agents as shown in colon cancer. However, biologic significance and relevance to I/O in metastatic clear cell RCC (ccRCC) are unknown. METHODS: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic ccRCC. Tumor and germline DNA were subject to targeted next generation sequencing across >400 genes of interest, including 34 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) deleterious DDR gene alterations present (Del DDR); (2) wild-type (WT) and variants of unknown significance (VUS) DDR gene alterations present (WT/VUS DDR). Association between DDR status and therapeutic benefit was investigated separately for I/O and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. RESULTS: Del DDR were detected in 43/229 patients (19%). The most frequently altered genes were CHEK2 and ATM. Clonality analysis was performed in 27 somatic DDR mutations and 17 were clonal (63%). For patients with I/O treatment, Del DDR status was associated with superior overall survival (log-rank p=0.049); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Del DDR was 0.41 (95% CI: 0.14-1.14; p=0.09). No association was seen with VEGF-TKI treatment (log-rank p=0.903). CONCLUSION: Del DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Loss-of-function events in these genes may affect outcome with I/O therapy in metastatic RCC, and these hypothesis-generating results deserve further study.