RESUMEN
Modulation of DNA damage repair in lung squamous cell carcinoma (LUSC) can result in the generation of neoantigens and heightened immunogenicity. Therefore, understanding DNA damage repair mechanisms holds significant clinical relevance for identifying targets for immunotherapy and devising therapeutic strategies. Our research has unveiled that the tumor suppressor zinc finger protein 750 (ZNF750) in LUSC binds to the promoter region of tenascin C (TNC), leading to reduced TNC expression. This modulation may impact the malignant behavior of tumor cells and is associated with patient prognosis. Additionally, single-cell RNA sequencing (scRNA-seq) of LUSC tissues has demonstrated an inverse correlation between ZNF750/TNC expression levels and immunogenicity. Manipulation of the ZNF750-TNC axis in vitro within LUSC cells has shown differential sensitivity to CD8+ cells, underscoring its pivotal role in regulating cellular immunogenicity. Further transcriptome sequencing analysis, DNA damage repair assay, and single-strand break analyses have revealed the involvement of the ZNF750-TNC axis in determining the preference for homologous recombination (HR) repair or non-homologous end joining (NHEJ) repair of DNA damage. with involvement of the Hippo/ERK signaling pathway. In summary, this study sheds light on the ZNF750-TNC axis's role in DNA damage repair regulation in LUSC, laying a groundwork for future translational research in immune cell therapy for LUSC.
Asunto(s)
Carcinoma de Células Escamosas , Daño del ADN , Neoplasias Pulmonares , Tenascina , Humanos , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Tenascina/genética , Tenascina/metabolismo , Daño del ADN/inmunología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Regiones Promotoras Genéticas , Pronóstico , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismoRESUMEN
Genomic stability relies on a multifaceted and evolutionarily conserved DNA damage response (DDR). In multicellular organisms, an integral facet of the DDR involves the activation of the immune system to eliminate cells with persistent DNA damage. Recent research has shed light on a complex array of nucleic acid sensors crucial for innate immune activation in response to oncogenic stress-associated DNA damage, a process vital for suppressing tumor formation. Yet, these immune sensing pathways may also be co-opted to foster tolerance of chromosomal instability, thereby driving cancer progression. This review aims to provide an updated overview of how the innate immune system detects and responds to DNA damage. An improved understanding of the regulatory intricacies governing this immune response may uncover new avenues for cancer prevention and therapeutic intervention.
Asunto(s)
Daño del ADN , Reconocimiento de Inmunidad Innata , Neoplasias , Humanos , Daño del ADN/inmunología , Reparación del ADN , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patologíaRESUMEN
Adult-onset neurodegenerative diseases are often accompanied by evidence of a chronic inflammation that includes activation of microglial cells and altered levels of brain cytokines. Aspects of this response are likely secondary reactions to neurodegeneration, but for many illnesses the inflammation may itself be an early and even causative disease event. In such cases, the inflammation is referred to as "sterile" as it occurs in the absence of an actual bacterial or viral pathogen. A potent trigger of sterile inflammation in CNS microglia has been shown to be the presence of DNA in the cytoplasm (cytoDNA) induced either by direct DNA damage or by inhibited DNA repair. We have shown that cytoDNA comes from the cell nucleus as a result of insufficient DNA damage repair. Using wild-type and Atm-/- mouse microglia, we extend these observations here by showing that its genomic origins are not random, but rather are heavily biased toward transcriptionally inactive, intergenic regions, in particular repetitive elements and AT-rich sequences. Once released from the genome, in both males and females, we show that cytoDNA is actively exported to the cytoplasm by a CRM1-dependent mechanism. In the cytoplasm, it is degraded either by a cytosolic exonuclease, Trex1, or an autophagy pathway that ends with degradation in the lysosome. Blocking the accumulation of cytoDNA prevents the emergence of the sterile inflammation reaction. These findings offer new insights into the emergence of sterile inflammation and offer novel approaches that may be of use in combatting a wide range of neurodegenerative conditions.SIGNIFICANCE STATEMENT Sterile inflammation describes a state where the defenses of the immune system are activated in the absence of a true pathogen. A potent trigger of this unorthodox response is the presence of DNA in the cytoplasm, which immune cells interpret as an invading virus or pathogen. We show that when DNA damage increases, fragments of the cell's own genome are actively exported to the cytoplasm where they are normally degraded. If this degradation is incomplete an immune reaction is triggered. Both age and stress increase DNA damage, and as age-related neurodegenerative diseases are frequently accompanied by a chronic low-level inflammation, strategies that reduce the induction of cytoplasmic DNA or speed its clearance become attractive therapeutic targets.
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Citoplasma/inmunología , Daño del ADN/inmunología , ADN/inmunología , Inflamación/inmunología , Secuencias Repetitivas de Ácidos Nucleicos/inmunología , Animales , Citoplasma/metabolismo , ADN/metabolismo , Reparación del ADN , Femenino , Inflamación/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microglía/inmunología , Microglía/metabolismoRESUMEN
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
18F-fluorodeoxyglucose PET-CT may guide treatment decisions in patients with oesophageal adenocarcinoma (OAC). This study evaluated the added value of maximum standardised uptake value (SUVmax) to a novel DNA-damage immune response (DDIR) assay to improve pathological response prediction. The diagnostic accuracy of PET response and the prognostic significance of PET metrics for recurrence-free survival (RFS) and overall survival (OS) were assessed. This was a retrospective, single-centre study of OAC patients treated with neo-adjuvant chemotherapy from 2003 to 2014. SUVmax was recorded from baseline and repeat PET-CT after completion of pre-operative chemotherapy. Logistic regression models tested the additional predictive value of PET metrics combined with the DDIR assay for pathological response. Cox regression models tested the prognostic significance of PET metrics for RFS and OS. In total, 113 patients were included; 25 (22.1%) were DDIR positive and 88 (77.9%) were DDIR negative. 69 (61.1%) were PET responders (SUVmax reduction of 35%) and 44 (38.9%) were PET non-responders. After adding PET metrics to DDIR status, post-chemotherapy SUVmax (hazard ratio (HR) 0.75, p = 0.02), SUVmax change (HR 1.04, p = 0.003) and an optimum SUVmax reduction of 46.5% (HR 4.36, p = 0.021) showed additional value for predicting pathological response. The optimised SUVmax threshold was independently significant for RFS (HR 0.47, 95% CI 0.26-0.85, p = 0.012) and OS (HR 0.51, 95% CI 0.26-0.99, p = 0.047). This study demonstrated the additional value of PET metrics, when combined with a novel DDIR assay, to predict pathological response in OAC patients treated with neo-adjuvant chemotherapy. Furthermore, an optimised SUVmax reduction threshold for pathological response was calculated and was independently significant for RFS and OS.
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Adenocarcinoma/diagnóstico por imagen , Adenocarcinoma/tratamiento farmacológico , Biomarcadores de Tumor/metabolismo , Daño del ADN/inmunología , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/tratamiento farmacológico , Inmunoensayo , Terapia Neoadyuvante , Tomografía de Emisión de Positrones , Adenocarcinoma/inmunología , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Neoplasias Esofágicas/inmunología , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/patología , Valor Predictivo de las Pruebas , Modelos de Riesgos Proporcionales , Sensibilidad y Especificidad , Análisis de SupervivenciaRESUMEN
In addition to its pivotal role in purine metabolism, xanthine oxidoreductase (XOR) is one of the key enzymes involved in superoxide radical generation. Oxidative stress has been implicated in the etiology of colorectal cancer, but the contribution of XOR remains unclear. Here we investigated the role of XOR in colitis-associated colorectal cancer (CAC) and the underlying mechanisms. Using clinical samples, we demonstrated that XOR up-regulation was an early event in colonic carcinogenesis. Pharmacological inhibition of XOR effectively delayed the progression of CAC. Moreover, XOR activity positively correlated with tumor necrosis factor-alpha (TNFα) protein levels. Mechanistically, TNFα may activate XOR transcription via activator protein-1 and, thus, promote endogenous hydrogen peroxide generation, resulting in oxidative DNA damage in colon cancer cells. On the other hand, XOR may regulate the TNFα mRNA transcripts by mediating LPS-induced macrophage M1 polarization. Collectively, XOR promotes tumor development by programming the tumor microenvironment and stimulates CAC progression via DNA damage-induced genetic instability.
Asunto(s)
Neoplasias Asociadas a Colitis/inmunología , Daño del ADN/inmunología , Macrófagos/inmunología , Estrés Oxidativo/inmunología , Xantina Deshidrogenasa/metabolismo , Animales , Carcinogénesis/inducido químicamente , Carcinogénesis/inmunología , Línea Celular Tumoral , Neoplasias Asociadas a Colitis/genética , Neoplasias Asociadas a Colitis/patología , Colon/inmunología , Colon/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/inmunología , Humanos , Macrófagos/metabolismo , Masculino , Activación Transcripcional/inmunología , Microambiente Tumoral/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba , Xantina Deshidrogenasa/genéticaRESUMEN
BACKGROUND AND AIMS: Hepatitis C virus (HCV) leads to a high rate of chronic infection and T cell dysfunction. Although it is well known that chronic antigenic stimulation is a driving force for impaired T cell functions, the precise mechanisms underlying immune activation-induced T cell dysfunctions during HCV infection remain elusive. APPROACH AND RESULTS: Here, we demonstrated that circulating CD4+ T cells from patients who are chronically HCV-infected exhibit an immune activation status, as evidenced by the overexpression of cell activation markers human leukocyte antigen-antigen D-related, glucose transporter 1, granzyme B, and the short-lived effector marker CD127- killer cell lectin-like receptor G1+ . In contrast, the expression of stem cell-like transcription factor T cell factor 1 and telomeric repeat-binding factor 2 (TRF2) are significantly reduced in CD4+ T cells from patients who are chronically HCV-infected compared with healthy participants (HP). Mechanistic studies revealed that CD4+ T cells from participants with HCV exhibit phosphoinositide 3-kinase/Akt/mammalian target of rapamycin signaling hyperactivation on T cell receptor stimulation, promoting proinflammatory effector cell differentiation, telomeric DNA damage, and cellular apoptosis. Inhibition of Akt signaling during T cell activation preserved the precursor memory cell population and prevented inflammatory effector cell expansion, DNA damage, and apoptotic death. Moreover, knockdown of TRF2 reduced HP T cell stemness and triggered telomeric DNA damage and cellular apoptosis, whereas overexpression of TRF2 in CD4 T cells prevented telomeric DNA damage. CONCLUSIONS: These results suggest that modulation of immune activation through inhibiting Akt signaling and protecting telomeres through enhancing TRF2 expression may open therapeutic strategies to fine tune the adaptive immune responses in the setting of persistent immune activation and inflammation during chronic HCV infection.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Daño del ADN/inmunología , Hepacivirus/genética , Hepatitis C Crónica/genética , Hepatitis C Crónica/inmunología , Telómero/genética , Adulto , Anciano , Apoptosis/genética , Apoptosis/inmunología , Células Cultivadas , Daño del ADN/genética , Femenino , Técnicas de Silenciamiento del Gen/métodos , Hepatitis C Crónica/virología , Humanos , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Infección Persistente/genética , Infección Persistente/inmunología , Infección Persistente/virología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , ARN Viral/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Serina-Treonina Quinasas TOR/metabolismo , Proteína 2 de Unión a Repeticiones Teloméricas/genética , Proteína 2 de Unión a Repeticiones Teloméricas/metabolismo , Transducción Genética/métodos , Adulto JovenRESUMEN
Pseudorabies virus (PRV) is the causative pathogen of Aujeszky's disease in pigs. Although vaccination is currently applied to prevent the morbidity of PRV infection, new applications are urgently needed to control this infectious disease. Poly(ADP-ribose) polymerase 1 (PARP1) functions in DNA damage repair. We report here that pharmacological and genetic inhibition of PARP1 significantly influenced PRV replication. Moreover, we demonstrate that inhibition of PARP1 induced DNA damage response and antiviral innate immunity. Mechanistically, PARP1 inhibition-induced DNA damage response resulted in the release of double-stranded DNA (dsDNA) into the cytosol, where dsDNA interacted with cyclic GMP-AMP (cGAMP) synthase (cGAS). cGAS subsequently catalyzed cGAMP production to activate the STING/TBK1/IRF3 innate immune signaling pathway. Furthermore, challenge of mice with PARP1 inhibitor stimulated antiviral innate immunity and protected mice from PRV infection in vivo. Our results demonstrate that PARP1 inhibitors may be used as a new strategy to prevent Aujeszky's disease in pigs. IMPORTANCE Aujeszky's disease is a notifiable infectious disease of pigs and causes economic losses worldwide in the pig industry. The causative pathogen is PRV, which is a member of the subfamily Alphaherpesvirinae of the family Herpesviridae. PRV has a wide range of hosts, such as ruminants, carnivores, and rodents. More seriously, recent reports suggest that PRV can cause human endophthalmitis and encephalitis, which indicates that PRV may be a potential zoonotic pathogen. Although vaccination is currently the major strategy used to control the disease, new applications are also urgently needed for the pig industry and public health. We report here that inhibition of PARP1 induces DNA damage-induced antiviral innate immunity through the cGAS-STING signaling pathway. Therefore, PARP1 is a therapeutic target for PRV infection as well as alphaherpesvirus infection.
Asunto(s)
Antivirales/inmunología , Daño del ADN/inmunología , Inmunidad Innata/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasa-1/antagonistas & inhibidores , Seudorrabia/tratamiento farmacológico , Animales , Antivirales/farmacología , Línea Celular , Herpesvirus Suido 1/efectos de los fármacos , Herpesvirus Suido 1/fisiología , Humanos , Proteínas de la Membrana/metabolismo , Ratones , Nucleotidiltransferasas/metabolismo , Poli(ADP-Ribosa) Polimerasa-1/genética , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Seudorrabia/inmunología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Porcinos , Replicación Viral/efectos de los fármacosRESUMEN
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
The maintenance of genomic stability in multicellular organisms relies on the DNA damage response (DDR). The DDR encompasses several interconnected pathways that cooperate to ensure the repair of genomic lesions. Besides their repair functions, several DDR proteins have emerged as involved in the onset of inflammatory responses. In particular, several actors of the DDR have been reported to elicit innate immune activation upon detection of cytosolic pathological nucleic acids. Conversely, pattern recognition receptors (PRRs), initially described as dedicated to the detection of cytosolic immune-stimulatory nucleic acids, have been found to regulate DDR. Thus, although initially described as operating in specific subcellular localizations, actors of the DDR and nucleic acid immune sensors may be involved in interconnected pathways, likely influencing the efficiency of one another. Within this mini review, we discuss evidences for the crosstalk between PRRs and actors of the DDR. For this purpose, we mainly focus on cyclic GMP-AMP (cGAMP) synthetase (cGAS) and Interferon Gamma Inducible Protein 16 (IFI16), as major PRRs involved in the detection of aberrant nucleic acid species, and components of the DNA-dependent protein kinase (DNA-PK) complex, involved in the repair of double strand breaks that were recently described to qualify as potential PRRs. Finally, we discuss how the crosstalk between DDR and nucleic acid-associated Interferon responses cooperate for the fine-tuning of innate immune activation, and therefore dictate pathological outcomes. Understanding the molecular determinants of such cooperation will be paramount to the design of future therapeutic approaches.
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Daño del ADN/inmunología , Inmunidad Innata , Ácidos Nucleicos/inmunología , Transducción de Señal/inmunología , Citosol/inmunología , Citosol/metabolismo , Citosol/patología , Daño del ADN/genética , Humanos , Proteínas de la Membrana/inmunología , Receptores de Reconocimiento de Patrones/metabolismoRESUMEN
Tumors undergo dynamic immunoediting as part of a process that balances immunologic sensing of emerging neoantigens and evasion from immune responses. Tumor-infiltrating lymphocytes (TIL) comprise heterogeneous subsets of peripheral T cells characterized by diverse functional differentiation states and dependence on T-cell receptor (TCR) specificity gained through recombination events during their development. We hypothesized that within the tumor microenvironment (TME), an antigenic milieu and immunologic interface, tumor-infiltrating peripheral T cells could reexpress key elements of the TCR recombination machinery, namely, Rag1 and Rag2 recombinases and Tdt polymerase, as a potential mechanism involved in the revision of TCR specificity. Using two syngeneic invasive breast cancer transplantable models, 4T1 and TS/A, we observed that Rag1, Rag2, and Dntt in situ mRNA expression characterized rare tumor-infiltrating T cells. In situ expression of the transcripts was increased in coisogenic Mlh1-deficient tumors, characterized by genomic overinstability, and was also modulated by PD-1 immune-checkpoint blockade. Through immunolocalization and mRNA hybridization analyses, we detected the presence of rare TDT+RAG1/2+ cells populating primary tumors and draining lymph nodes in human invasive breast cancer. Analysis of harmonized single-cell RNA-sequencing data sets of human cancers identified a very small fraction of tumor-associated T cells, characterized by the expression of recombination/revision machinery transcripts, which on pseudotemporal ordering corresponded to differentiated effector T cells. We offer thought-provoking evidence of a TIL microniche marked by rare transcripts involved in TCR shaping.
Asunto(s)
Neoplasias de la Mama/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Recombinación Genética/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T/genética , Adulto , Anciano , Anciano de 80 o más Años , Animales , Mama/inmunología , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Linfocitos T CD8-positivos/metabolismo , Daño del ADN/inmunología , ADN Nucleotidilexotransferasa/genética , ADN Nucleotidilexotransferasa/metabolismo , Proteínas de Unión al ADN/metabolismo , Conjuntos de Datos como Asunto , Modelos Animales de Enfermedad , Femenino , Proteínas de Homeodominio/metabolismo , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Ratones , Ratones Noqueados , Persona de Mediana Edad , Homólogo 1 de la Proteína MutL/genética , Homólogo 1 de la Proteína MutL/metabolismo , Proteínas Nucleares/metabolismo , RNA-Seq , Receptores de Antígenos de Linfocitos T , Análisis de la Célula Individual , Microambiente Tumoral/genética , Microambiente Tumoral/inmunologíaRESUMEN
Tumor metastasis is a singularly important determinant of survival in most cancers. Historically, radiation therapy (RT) directed at a primary tumor mass was associated infrequently with remission of metastasis outside the field of irradiation. This away-from-target or "abscopal effect" received fringe attention because of its rarity. With the advent of immunotherapy, there are now increasing reports of abscopal effects upon RT in combination with immune checkpoint inhibition. This sparked investigation into underlying mechanisms and clinical trials aimed at enhancement of this effect. While these studies clearly attribute the abscopal effect to an antitumor immune response, the initial molecular triggers for its onset and specificity remain enigmatic. Here, we propose that DNA damage-induced inflammation coupled with neoantigen generation is essential during this intriguing phenomenon of systemic tumor regression and discuss the implications of this model for treatment aimed at triggering the abscopal effect in metastatic cancer.
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Daño del ADN/inmunología , ADN de Neoplasias/inmunología , Inmunoterapia , Neoplasias , Animales , Terapia Combinada , Humanos , Metástasis de la Neoplasia , Neoplasias/inmunología , Neoplasias/patología , Neoplasias/terapiaRESUMEN
The DNA damage response (DDR) fulfils essential roles to preserve genome integrity. Targeting the DDR in tumors has had remarkable success over the last decade, exemplified by the licensing of PARP inhibitors for cancer therapy. Recent studies suggest that the application of DDR inhibitors impacts on cellular innate and adaptive immune responses, wherein key DNA repair factors have roles in limiting chronic inflammatory signaling. Antitumor immunity plays an emerging part in cancer therapy, and extensive efforts have led to the development of immune checkpoint inhibitors overcoming immune suppressive signals in tumors. Here, we review the current understanding of the molecular mechanisms underlying DNA damage-triggered immune responses, including cytosolic DNA sensing via the cGAS/STING pathway. We highlight the implications of DDR components for therapeutic outcomes of immune checkpoint inhibitors or their use as biomarkers. Finally, we discuss the rationale for novel combinations of DDR inhibitors with antagonists of immune checkpoints and current hindrances limiting their broader therapeutic applications.
Asunto(s)
Reparación del ADN/fisiología , Inmunidad Celular/genética , Inmunoterapia , Neoplasias/terapia , Inmunidad Adaptativa/genética , Daño del ADN/inmunología , Receptores con Dominio Discoidina/antagonistas & inhibidores , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Chronic exposure to benzene is a risk factor for hematological malignancies. Gasoline-station workers are exposed to benzene in gasoline, via both inhalation and dermal contact (attendants and managers) or inhalation (workers in the on-site convenience stores and offices). We have studied the exposure of these workers to benzene and the resulting genotoxic and immunotoxic effects. Levels of urinary trans, trans-muconic acid were higher among gasoline-station workers than among office workers with no known exposure to benzene (comparison group). Among the exposed workers, we observed statistically significant biological effects, including elevated DNA damage (comet assay); higher frequencies of micronuclei and nuclear buds (CBMN assay); lower levels of T-helper lymphocytes and naive Th lymphocytes; lower CD4 / CD8 ratio; and higher levels of NK cells and memory Th lymphocytes. Both groups of exposed workers (inhalation and inhalation + dermal routes) showed similar genotoxic and immunotoxic effects.
Asunto(s)
Benceno/toxicidad , Gasolina/toxicidad , Sistema Inmunológico/efectos de los fármacos , Exposición Profesional , Adulto , Anciano , Contaminantes Ocupacionales del Aire/toxicidad , Brasil/epidemiología , Ensayo Cometa , Estudios Transversales , Daño del ADN/efectos de los fármacos , Daño del ADN/inmunología , Femenino , Humanos , Sistema Inmunológico/metabolismo , Inmunomodulación/efectos de los fármacos , Exposición por Inhalación/efectos adversos , Exposición por Inhalación/análisis , Recuento de Linfocitos , Masculino , Pruebas de Micronúcleos , Persona de Mediana Edad , Pruebas de Mutagenicidad , Exposición Profesional/efectos adversos , Exposición Profesional/análisis , Exposición Profesional/estadística & datos numéricos , Estrés Fisiológico/efectos de los fármacos , Estrés Fisiológico/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/patología , Adulto JovenRESUMEN
Radiation therapy (RT) in some cases results in a systemic anticancer response known as the abscopal effect. Multiple hypotheses support the role of immune activation initiated by RT-induced DNA damage. Optimal radiation dose is necessary to promote the cGAS-STING pathway in response to radiation and initiate an IFN-1 signaling cascade that promotes the maturation and migration of dendritic cells to facilitate antigen presentation and stimulation of cytotoxic T cells. T cells then exert a targeted response throughout the body at areas not subjected to RT. These effects are further augmented through the use of immunotherapeutic drugs resulting in increased T-cell activity. Tumor-infiltrating lymphocyte presence and TREX1, KPNA2 and p53 signal expression are being explored as prognostic biomarkers.
Asunto(s)
Quimioradioterapia/métodos , Células Dendríticas/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/radioterapia , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Movimiento Celular/efectos de la radiación , Ensayos Clínicos como Asunto , Daño del ADN/inmunología , Daño del ADN/efectos de la radiación , Células Dendríticas/efectos de la radiación , Exodesoxirribonucleasas/análisis , Exodesoxirribonucleasas/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/efectos de la radiación , Neoplasias/genética , Neoplasias/inmunología , Neoplasias/mortalidad , Fosfoproteínas/análisis , Fosfoproteínas/metabolismo , Pronóstico , Supervivencia sin Progresión , Dosificación Radioterapéutica , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Linfocitos T/efectos de la radiación , Microambiente Tumoral/efectos de los fármacos , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiación , Proteína p53 Supresora de Tumor/análisis , Proteína p53 Supresora de Tumor/metabolismo , alfa Carioferinas/análisis , alfa Carioferinas/metabolismoRESUMEN
Tachykinin-related peptides (TRPs) are important neuropeptides. Here we show that they affect the insect immune system, especially the cellular response. We also identify and predict the sequence and structure of the tachykinin-related peptide receptor (TRPR) and confirm the presence of expression of gene encoding TRPR on Tenebrio molitor haemocytes. After application of the Tenmo-TRP-7 in T. molitor the number of circulating haemocytes increased and the number of haemocytes participating in phagocytosis of latex beads decreased in a dose- and time-dependent fashion. Also, Tenmo-TRP-7 affects the adhesion ability of haemocytes. Six hours after injection of Tenmo-TRP-7, a decrease of haemocyte surface area was observed under both tested Tenmo-TRP-7 concentrations (10-7 and 10-5 M). The opposite effect was reported 24 h after injection, which indicates that the influence of Tenmo-TRP-7 on modulation of haemocyte behaviour differs at different stages of stress response. Tenmo-TRP-7 application also resulted in increased phenoloxidase activity 6 and 24 h after injection. The assessment of DNA integrity of haemocytes showed that the injection of Tenmo-TRP-7 at 10-7 M led to a decrease in DNA damage compared to control individuals. This effect was only visible 6 h after Tenmo-TRP-7 application. After 24 h, Tenmo-TRP-7 injection increased DNA damage. We also confirmed the expression of immune-related genes in nervous tissue of T. molitor. Transcripts for genes encoding receptors participating in pathogen recognition processes and antimicrobial peptides were detected in T. molitor brain, retrocerebral complex and ventral nerve cord. These results may indicate a role of the insect nervous system in pathogen recognition and modulation of immune response similar to vertebrates. Taken together, our results support the notion that tachykinin-related peptides probably play an important role in the regulation of the insect immune system. Moreover, some resemblances with action of tachykinin-related peptides and substance P showed that insects can be potential model organisms for analysis of hormonal regulation of conserved innate immune mechanisms.
Asunto(s)
Péptidos Antimicrobianos/metabolismo , Hemocitos/inmunología , Proteínas de Insectos/metabolismo , Taquicininas/metabolismo , Tenebrio/inmunología , Animales , Daño del ADN/inmunología , Hemocitos/metabolismo , Monofenol Monooxigenasa/metabolismo , Fagocitosis , Receptores de Taquicininas/metabolismo , Tenebrio/genética , Tenebrio/metabolismoAsunto(s)
Proteínas de la Ataxia Telangiectasia Mutada , Daño del ADN , ADN de Neoplasias , Proteínas de Neoplasias , Proteínas Nucleares , Neoplasias de la Próstata/inmunología , Proteínas Represoras , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteínas de la Ataxia Telangiectasia Mutada/inmunología , Daño del ADN/genética , Daño del ADN/inmunología , ADN de Neoplasias/genética , ADN de Neoplasias/inmunología , Humanos , Masculino , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/inmunología , Proteínas Nucleares/genética , Proteínas Nucleares/inmunología , Neoplasias de la Próstata/genética , Proteínas Represoras/genética , Proteínas Represoras/inmunologíaRESUMEN
The developmental origins of memory T cells remain incompletely understood. During the expansion phase of acute viral infection, we identified a distinct subset of virus-specific CD8+ T cells that possessed distinct characteristics including expression of CD62L, T cell factor 1 (TCF-1), and Eomesodermin; relative quiescence; expression of activation markers; and features of limited effector differentiation. These cells were a quantitatively minor subpopulation of the TCF-1+ pool and exhibited self-renewal, heightened DNA damage surveillance activity, and preferential long-term recall capacity. Despite features of memory and somewhat restrained proliferation during the expansion phase, this subset displayed evidence of stronger TCR signaling than other responding CD8+ T cells, coupled with elevated expression of multiple inhibitory receptors including programmed cell death 1 (PD-1), lymphocyte activating gene 3 (LAG-3), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), CD5, and CD160. Genetic ablation of PD-1 and LAG-3 compromised the formation of this CD62Lhi TCF-1+ subset and subsequent CD8+ T cell memory. Although central memory phenotype CD8+ T cells were formed in the absence of these cells, subsequent memory CD8+ T cell recall responses were compromised. Together, these results identify an important link between genome integrity maintenance and CD8+ T cell memory. Moreover, the data indicate a role for inhibitory receptors in preserving key memory CD8+ T cell precursors during initial activation and differentiation. Identification of this rare subpopulation within the memory CD8+ T cell precursor pool may help reconcile models of the developmental origin of long-term CD8+ T cell memory.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Listeriosis/inmunología , Coriomeningitis Linfocítica/inmunología , Células T de Memoria/inmunología , Células Precursoras de Linfocitos T/inmunología , Animales , Antígenos CD/genética , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Daño del ADN/inmunología , Modelos Animales de Enfermedad , Femenino , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Memoria Inmunológica/genética , Listeria monocytogenes/inmunología , Listeriosis/microbiología , Activación de Linfocitos , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/inmunología , Masculino , Células T de Memoria/metabolismo , Ratones , Ratones Noqueados , Células Precursoras de Linfocitos T/metabolismo , Receptor de Muerte Celular Programada 1/genética , Proteína del Gen 3 de Activación de LinfocitosRESUMEN
NAD+ was discovered during yeast fermentation, and since its discovery, its important roles in redox metabolism, aging, and longevity, the immune system and DNA repair have been highlighted. A deregulation of the NAD+ levels has been associated with metabolic diseases and aging-related diseases, including neurodegeneration, defective immune responses, and cancer. NAD+ acts as a cofactor through its interplay with NADH, playing an essential role in many enzymatic reactions of energy metabolism, such as glycolysis, oxidative phosphorylation, fatty acid oxidation, and the TCA cycle. NAD+ also plays a role in deacetylation by sirtuins and ADP ribosylation during DNA damage/repair by PARP proteins. Finally, different NAD hydrolase proteins also consume NAD+ while converting it into ADP-ribose or its cyclic counterpart. Some of these proteins, such as CD38, seem to be extensively involved in the immune response. Since NAD cannot be taken directly from food, NAD metabolism is essential, and NAMPT is the key enzyme recovering NAD from nicotinamide and generating most of the NAD cellular pools. Because of the complex network of pathways in which NAD+ is essential, the important role of NAD+ and its key generating enzyme, NAMPT, in cancer is understandable. In the present work, we review the role of NAD+ and NAMPT in the ways that they may influence cancer metabolism, the immune system, stemness, aging, and cancer. Finally, we review some ongoing research on therapeutic approaches.
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NAD/inmunología , Neoplasias/inmunología , Células Madre Neoplásicas/inmunología , Ciclo del Ácido Cítrico/inmunología , Citocinas/inmunología , Daño del ADN/inmunología , Humanos , Proteínas de Neoplasias/inmunología , Neoplasias/terapia , Nicotinamida Fosforribosiltransferasa/inmunologíaRESUMEN
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.