The MICA-NKG2D axis in clear cell renal cell carcinoma bolsters MICA as target in immuno-oncology.

NKG2D is a major natural killer (NK) cell-activating receptor that recognizes eight ligands (NKG2DLs), including MICA, and whose engagement triggers NK cell effector functions. As NKG2DLs are upregulated on tumor cells but tumors can subvert the NKG2D-NKG2DL axis, NKG2DLs constitute attractive targets for antibody (Ab)-based immuno-oncology therapies. However, such approaches require a deep characterization of NKG2DLs and NKG2D cell surface expression on primary tumor and immune cells. Here, using a bioinformatic analysis, we observed that MICA is overexpressed in renal cell carcinoma (RCC), and we also detected an association between the NKG2D-MICA axis and a diminished overall survival of RCC patients. Also, by flow cytometry (FC), we observed that MICA was the only NKG2DL over-expressed on clear cell renal cell carcinoma (ccRCC) tumor cells, including cancer stem cells (CSC) that also coexpressed NKG2D. Moreover, tumor-infiltrating leukocytes (TIL), but not peripheral blood lymphoid cells (PBL) from ccRCC patients, over-expressed MICA, ULBP3 and ULBP4. In addition, NKG2D was downregulated on peripheral blood NK cells (PBNK) from ccRCC patients but upregulated on tumor-infiltrating NK cells (TINK). These TINK exhibited impaired degranulation that negatively correlated with NKG2D expression, diminished IFN-γ production, upregulation of TIM-3, and an impaired glucose intake upon stimulation with cytokines, indicating that they are dysfunctional, display features of exhaustion and an altered metabolic fitness. We conclude that ccRCC patients exhibit a distorted MICA-NKG2D axis, and MICA emerges as the forefront NKG2DL for the development of targeted therapies in ccRCC.

Circulating and Tumor-Infiltrating NK Cells From Clear Cell Renal Cell Carcinoma Patients Exhibit a Predominantly Inhibitory Phenotype Characterized by Overexpression of CD85j, CD45, CD48 and PD-1.

Although natural killer (NK) cells infiltrate clear cell renal cell carcinomas (ccRCC), the most frequent malignancy of the kidney, tumor progression suggests that they become dysfunctional. As ccRCC-driven subversion of NK cell effector functions is usually accompanied by phenotypic changes, analysis of such alterations might lead to the identification of novel biomarkers and/or targets in immuno-oncology. Consequently, we performed a phenotypic analysis of peripheral blood NK cells (PBNK) and tumor-infiltrating NK cells (TINK) from ccRCC patients. Compared to HD, PBNK from ccRCC patients exhibited features of activated cells as shown by CD25, CD69 and CD62L expression. They also displayed increased expression of DNAM-1, CD48, CD45, MHC-I, reduced expression of NKG2D, and higher frequencies of CD85j+ and PD-1+ cells. In addition, compared to PBNK from ccRCC patients, TINK exhibited higher expression of activation markers, tissue residency features and decreased expression of the activating receptors DNAM-1, NKp30, NKp46, NKp80 and CD16, suggesting a more inhibitory phenotype. Analysis of The Cancer Genome Atlas (TCGA) revealed that CD48, CD45, CD85j and PD-1 are significantly overexpressed in ccRCC and that their expression is associated with an NK cell infiltration signature. Calculation of z-scores revealed that their expression on PBNK, alone or combined, distinguished ccRCC patients from HD. Therefore, these molecules emerge as novel potential biomarkers and our results suggest that they might constitute possible targets for immunotherapy in ccRCC patients.

Comparing Taguchi and Lich-Gregoir ureterovesical reimplantation techniques for kidney transplants.

PURPOSE: We compared the incidence of urological and anastomotic complications, and the duration of ureteral reimplantation for the Taguchi and Lich-Gregoir techniques. MATERIALS AND METHODS: We recorded all urological and anastomotic complications that developed from the date of transplantation through December 31, 2001. The cutoff date for transplantation was August 30, 2000. The urological complications evaluated included complicated hematuria, urinary fistula, ureteral stenosis, symptomatic vesicoureteral reflux and operative time. The chi-square test was done to compare the proportion of complications in the groups and the Mann Whitney test was used to compare the duration of ureteral reimplantation. RESULTS: Of the 575 transplants evaluated 416 and 159 were performed via the Lich-Gregoir and Taguchi techniques, respectively. The incidence of anastomotic complications was 10.7%. Complications in the Lich-Gregoir group included fistula in 4.7% of cases, stenosis in 4.1%, symptomatic vesicoureteral reflux in 1.9% and complicated hematuria in 0.5%. Complications in the Taguchi group included urinary fistula in 6.3% of cases, stenosis in 2.5% and complicated hematuria in 2.5%. Symptomatic reflux was not observed in this group. There was a higher proportion of hematuria at the limit of statistical significance in the Taguchi group (p = 0.05). There were a higher number of urological complications in transplants from live donors in the Lich-Gregoir group (p = 0.01), mostly involving fistula (p = 0.05). There were no significant differences in the groups in overall complications. Average operative time for the Taguchi and Lich-Gregoir techniques was 14.2 and 29 minutes, respectively. This difference was significant (p = 0.02). CONCLUSIONS: In the sample studied Taguchi ureterocystoneostomy proved to be a more rapid method without increasing the incidence of urological or anastomotic complications. There were no cases of symptomatic reflux in the Taguchi group and select fistula cases could be managed conservatively. The Lich-Gregoir cohort was at greater risk for the urological complications of live donor transplantation. The Taguchi method has become the ureterovesical reimplantation technique of choice in our setting.

[Value of gray scale ultrasonography in the early diagnosis of urologic complications of renal transplantation]. / Valor de la ultrasonografía en escala de grises en el diagnóstico precoz de las complicaciones urológicas del trasplante renal.

OBJECTIVE: To determine the significance of gray scale ultrasound as a tool for diagnosis, follow-up and treatment of urological complications of renal transplantation based on the experience of our institution. METHODS: A retrospective, longitudinal and observational study was carried out. We reviewed the patients' perioperative ultrasound scans and their respective urological complications from January 1, 1982 to January 1, 2000. The patients were consecutively taken from the kidney transplant registry of the Urology and Nephrology and Transplant Departments. We describe the ultrasound findings of normal functioning grafts as well as those with urological complications, such as fluid collections (lymphocele, hematoma, urinoma and abscess), uronephrosis and its possible causes, and symptomatic vesicourethral reflux. RESULTS/CONCLUSIONS: Diagnostic and therapeutic algorithms in kidney transplant patients have been changed since the advent of ultrasound in our country in 1981. Rapid diagnosis and better therapeutic options have been the hallmarks of ultrasound. Added advantages are: it is low-cost, non-invasive, not time consuming. It can be performed regardless of kidney function, can be repeated as many times as required, subsequent scans can be compared. It can be carried out in special care units. The superficial location of the graft makes it highly sensitive. Its disadvantages are low specificity to identify either the nature of the fluid collections or the precise site of urinary tract obstruction, apart from depending on the skill of the operator. Specialists should be familiar with the surgical anatomy of the kidney graft and its variations in order to utilize completely its diagnostic and therapeutic potentials.

Valor de la ultrasonografía en escala de grises en el diagnóstico precoz de las complicaciones urológicas del trasplante renal / Value of gray scale ultrasonography in the early diagnosis of the urological complications of renal transplantation

Objetivo: Establecer el valor de la ecografía en escala de grises para el diagnóstico, seguimiento y eventual tratamiento de las complicaciones urológicas del trasplante renal basado en la experiencia de nuestro centro. Métodos: Se revisaron los informes ecográficos y las complicaciones urológicas de los pacientes trasplantados desde el 1 de enero de 1982 hasta el 1 de enero del 2000. El muestreo fue consecutivo, no probabilístico en base a los registros documentados en la sección Urología y en el Servicio de Nefrología y Trasplante de la Institución. El diseño fue retrospectivo, longitudinal y observacional. Resultados: Se describen los hallazgos ecográficos de injertos con buen funcionamiento y aquellos con complicaciones urológicas, a saber: colecciones (linfoceles, hematomas, urinomas y abscesos), uronefrosis con sus posibles causas y reflujo sintomático. Conclusiones: Desde el advenimiento de la ecografía en nuestro país en 1981 se han modificado tanto los algorritmos diagnósticos como los tiempos terapéuticos en esta población de pacientes. Se ha ganado en precocidad diagnóstica y mayor serenidad al momento de decidir por un tratamiento, dado por un sin fin de ventajas: bajo costo, no invasividad, rápida realización, no altera ni perjudica la función del injerto, puede repetirse cuantas veces sea necesario lo que hace que los sucesivos estudios sean comparables entre sí, al ser portátil puede llevarse a cabo dentro de las áreas especiales para pacientes inmunosuprimidos y la localización superficial del injerto contribuye a hacer de este un procedimiento altamente sensible. Sus desventajas son su baja especificidad para distinguir el contenido de las colecciones o el nivel exacto de las obstrucciones, y el hecho de ser un procedimiento operador dependiente. El buen especialista debe estar profundamente familiarizado con la anatomía quirúrgica del trasplante y sus variantes a los efectos de obtener de la ecografía el 100 por ciento de su potencial diagnóstico y terapéutico (AU)