RESUMEN
Spontaneous T cell responses against tumors occur frequently and have prognostic value in patients. The mechanism of innate immune sensing of immunogenic tumors leading to adaptive T cell responses remains undefined, although type I interferons (IFNs) are implicated in this process. We found that spontaneous CD8(+) T cell priming against tumors was defective in mice lacking stimulator of interferon genes complex (STING), but not other innate signaling pathways, suggesting involvement of a cytosolic DNA sensing pathway. In vitro, IFN-? production and dendritic cell activation were triggered by tumor-cell-derived DNA, via cyclic-GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3). In the tumor microenvironment in vivo, tumor cell DNA was detected within host antigen-presenting cells, which correlated with STING pathway activation and IFN-? production. Our results demonstrate that a major mechanism for innate immune sensing of cancer occurs via the host STING pathway, with major implications for cancer immunotherapy.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , ADN/inmunología , Activación de Linfocitos/inmunología , Melanoma Experimental/inmunología , Proteínas de la Membrana/inmunología , Inmunidad Adaptativa , Proteínas Adaptadoras Transductoras de Señales/genética , Traslado Adoptivo , Animales , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunología , Línea Celular Tumoral , Proliferación Celular , Células Dendríticas/inmunología , Inmunidad Innata , Factor 3 Regulador del Interferón/genética , Interferón beta/biosíntesis , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor 88 de Diferenciación Mieloide/genética , Nucleotidiltransferasas , Receptores de Antígenos de Linfocitos T/inmunología , Receptores Purinérgicos P2X7/genética , Receptor Toll-Like 4/genética , Receptor Toll-Like 9/genética , Microambiente Tumoral/inmunologíaRESUMEN
OBJECTIVE: The quality of primary care delivered to Medicaid-insured children with disabilities (CWD) is unknown. We used the newly validated CWD algorithm (CWDA) to examine CWD prevalence among Medicaid enrollees 1 to 18 years old, primary care quality for CWD, and differences in primary care quality for CWD and non-CWD. METHODS: Cross-sectional study using 2008 Medicaid Analytic eXtract claims data from 9 states, including children with at least 11 months of enrollment (N = 2,671,922 enrollees). We utilized CWDA to identify CWD and applied 12 validated or endorsed pediatric quality measures to assess preventive/screening, acute, and chronic disease care quality. We compared quality for CWD and non-CWD unmatched and matched on age, sex, and number of nondisabling chronic conditions and outpatient encounters. RESULTS: CWDA identified 5.3% (n = 141,384) of our study population as CWD. Care quality levels for CWD were below 50% on 8 of 12 quality measures (eg, adolescent well visits [44.9%], alcohol/drug treatment engagement [24.9%]). CWD care quality was significantly better than the general population of non-CWD by +0.9% to +15.6% on 9 measures, but significantly worse for 2 measures, chlamydia screening (-3.4%) and no emergency department visits for asthma (-5.0%; all P < .01 to .001). Differences in care quality between CWD and non-CWD were generally smaller or changed direction when CWD were compared to a general population or matched group of non-CWD. CONCLUSIONS: One in 20 Medicaid-insured children is CWD, and the quality of primary care delivered to CWD is suboptimal. Areas needing improvement include preventive/screening, acute care, and chronic disease management.