RESUMEN
A clearer understanding of the tumor immune microenvironment (TIME) in metastatic clear cell renal cell carcinoma (ccRCC) may help to inform precision treatment strategies. We sought to identify clinically meaningful TIME signatures in ccRCC. We studied tumors from 39 patients with metastatic ccRCC using quantitative multiplexed immunofluorescence and relevant immune marker panels. Cell densities were analyzed in three regions of interest (ROIs): tumor core, tumor-stroma interface and stroma. Patients were stratified into low- and high-marker density groups using median values as thresholds. Log-rank and Cox regression analyses while controlling for clinical variables were used to compare survival outcomes to patterns of immune cell distributions. There were significant associations with increased macrophage (CD68+ CD163+ CD206+ ) density and poor outcomes across multiple ROIs in primary and metastatic tumors. In primary tumors, T-bet+ T helper type 1 (Th1) cell density was highest at the tumor-stromal interface (P = 0·0021), and increased co-expression of CD3 and T-bet was associated with improved overall survival (P = 0·015) and survival after immunotherapy (P = 0·014). In metastatic tumor samples, decreased forkhead box protein 3 (FoxP3)+ T regulatory cell density correlated with improved survival after immunotherapy (P = 0·016). Increased macrophage markers and decreased Th1 T cell markers within the TIME correlated with poor overall survival and treatment outcomes. Immune markers such as FoxP3 showed consistent levels across the TIME, whereas others, such as T-bet, demonstrated significant variance across the distinct ROIs. These findings suggest that TIME profiling outside the tumor core may identify clinically relevant associations for patients with metastatic ccRCC.
Asunto(s)
Carcinoma de Células Renales/terapia , Inmunoterapia/métodos , Neoplasias Renales/terapia , Microambiente Tumoral/inmunología , Adulto , Anciano , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/metabolismo , Femenino , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Sistema Inmunológico/patología , Estimación de Kaplan-Meier , Neoplasias Renales/inmunología , Neoplasias Renales/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Masculino , Persona de Mediana Edad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Resultado del TratamientoRESUMEN
Treatment of rats between day 15 and 20 of gestation with gentamicin caused histological as well as enzyme histochemical lesions in the kidney of the one year old offspring (F1 generation). Other organs were not significantly affected. Primarily in the female kidney dilated convoluted proximal tubulus with reduced or absent staining for brush border and lysosomal proteases, phosphatases and glycosidases and mitochondrial dehydrogenases were observed. In comparison, glomeruli were less frequently damaged and contained fewer capillary loops or irregularly arranged tissue elements with lowered or no activities for plasma membrane-associated proteases as well as specific and non-specific phosphatases. In addition, the activities of proteases and phosphatases in cortical and medullary endothelial cells of capillaries were reduced or even abolished in the kidney of the female and male F1 generation after treatment of their mothers with gentamicin.