Ketogenic diet enhances the anti-cancer effects of PD-L1 blockade in renal cell carcinoma.

Introduction: Clear cell renal cell carcinoma (ccRCC) is characterized by a predominant metabolic reprogramming triggering energy production by anaerobic glycolysis at the expense of oxydative phosphorylation. Ketogenic diet (KD), which consists of high fat and low carbohydrate intake, could bring required energy substrates to healthy cells while depriving tumor cells of glucose. Our objective was to evaluate the effect of KD on renal cancer cell tumor metabolism and growth proliferation. Methods: Growth cell proliferation and mitochondrial metabolism of ACHN and Renca renal carcinoma cells were evaluated under ketone bodies (KB) exposure. In vivo studies were performed with mice (nude or Balb/c) receiving a xenograft of ACHN cells or Renca cells, respectively, and were then split into 2 feeding groups, fed either with standard diet or a 2:1 KD ad libitum. To test the effect of KD associated to immunotherapy, Balb/c mice were treated with anti-PDL1 mAb. Tumor growth was monitored. Results: In vitro, KB exposure was associated with a significant reduction of ACHN and Renca cell proliferation and viability, while increasing mitochondrial metabolism. In mice, KD was associated with tumor growth reduction and PDL-1 gene expression up-regulation. In Balb/c mice adjuvant KD was associated to a better response to anti-PDL-1 mAb treatment. Conclusion: KB reduced the renal tumor cell growth proliferation and improved mitochondrial respiration and biogenesis. KD also slowed down tumor growth of ACHN and Renca in vivo. We observed that PDL-1 was significantly overexpressed in tumor in mice under KD. Response to anti-PDL-1 mAb was improved in mice under KD. Further studies are needed to confirm the therapeutic benefit of adjuvant KD combined with immunotherapy in patients with kidney cancer.

[2022 WHO classification of renal cell carcinomas: Focus on papillary renal cell carcinoma]. / Classification OMS 2022 des cancers du rein : focus sur le carcinome rénal papillaire.

Renal cell carcinomas (RCC) represent a group of heterogeneous tumors whose classification has greatly evolved since 1981. The latest update in 2022 classifies all renal cell carcinomas into six categories according to their morphology or the detection of specific molecular alterations. Molecular disassembly of renal cell carcinomas with papillary features has enabled the identification of new entities characterized by a specific molecular alteration, such as Fumarate Hydratase (FH) deficient RCC, TFE3-rearranged RCC or TFEB-altered RCC. This new classification allows for a more accurate diagnosis but requires a thorough knowledge of the genomic alterations to search for with immunohistochemical or molecular biology techniques. According to the new WHO 2022 classification, papillary renal cell carcinoma (PRC) type 1 or type 2 classification is no longer recommended. A classification based on nucleolar ISUP grade must be preferred: low-grade PRC (ISUP 1-2) or high-grade PRC (ISUP 3-4). The other prognostic factors remain the same: the pTNM stage, lymphovascular invasion, and the presence or absence of dedifferentiated areas referring to sarcomatoid or rhabdoid features. Of note, the presence of necrosis is not currently recognized as a poor prognostic element for this type of carcinoma. The diagnosis of high-grade PRC is from now on a diagnosis of exclusion. It can only be sustained after having ruled out TFE3-rearranged RCC, TFEB-altered RCC, and FH-deficient RCC. For clinicians, the diagnosis of PRC implies suggesting an oncogenetic consultation to screen for an associated genetic tumor syndrome regardless of the patient's age.

[Surgical and pathological consequences of preoperative immunotherapy in onco-urology]. / Conséquences chirurgicales et anatomopathologiques de l'immunothérapie préopératoire en onco-urologie.

INTRODUCTION: Patients treated with immunotherapy might need surgical procedures in addition to the medical treatment. The main indications are cytoreductive nephrectomy, cystectomy (as part of clinical trials) and metastasis removal in some oligometastatic patients. This study aims to assess the feasibility of surgery for patients treated by immunotherapy and describes the histological modifications found in the pathological analysis. MATERIAL AND METHODS: We conducted a retrospective, monocentric study. We included all patients operated for a urologic cancer and previously treated with systemic immunotherapy between February 2018 and June 2022. We compared this population with a control group of patients treated with surgery without having previous immunotherapy. Patients were compared according to the cancer type, age and sex. We compared perioperative complications. We performed an analysis for evaluation of the peri-tumoral inflammatory infiltration. RESULTS: We included 50 patients in this study. The two groups were comparable in age (63.7 vs. 63.3years old, P=0.95) and sex (4 and 6 women in the first and second group). The peroperatory complication rate was comparable (20% vs. 16%, P=1). The mean bleeding volume was comparable (664 vs. 629mL; P=0.89). The postoperative complication rate (48% vs. 56%; P=0.78) and their grade (Clavien III-IV 8% vs. 24%; P=0.24) were comparable. The anatomopathological analysis described the same rate and intensity of peri-tumoral inflammatory infiltrate (96% vs. 96%; P=1). CONCLUSIONS: Preoperative immunotherapy does not appear to be associated with increased surgical difficulty and perioperative complications. Blind histological analysis of the surgical specimens did not reveal any specific features related to pre operative immunotherapy. LEVEL OF EVIDENCE: Grade 3 HAS.

Effects of Large Extracellular Vesicles from Kidney Cancer Patients on the Growth and Environment of Renal Cell Carcinoma Xenografts in a Mouse Model.

Plasma membrane-derived vesicles, also referred to as large extracellular vesicles (lEVs), are implicated in several pathophysiological situations, including cancer. However, to date, no studies have evaluated the effects of lEVs isolated from patients with renal cancer on the development of their tumors. In this study, we investigated the effects of three types of lEVs on the growth and peritumoral environment of xenograft clear cell renal cell carcinoma in a mouse model. Xenograft cancer cells were derived from patients' nephrectomy specimens. Three types of lEVs were obtained from pre-nephrectomy patient blood (cEV), the supernatant of primary cancer cell culture (sEV) and from blood from individuals with no medical history of cancer (iEV). Xenograft volume was measured after nine weeks of growth. Xenografts were then removed, and the expression of CD31 and Ki67 were evaluated. We also measured the expression of MMP2 and Ca9 in the native mouse kidney. lEVs from kidney cancer patients (cEV and sEV) tend to increase the size of xenografts, a factor that is related to an increase in vascularization and tumor cell proliferation. cEV also altered organs that were distant from the xenograft. These results suggest that lEVs in cancer patients are involved in both tumor growth and cancer progression.