Pathological RANK signaling in B cells drives autoimmunity and chronic lymphocytic leukemia

Clinical evidence suggests alterations in receptor activator of NF-κB (RANK) signaling are key contributors to B cell autoimmunity and malignancy, but the pathophysiological consequences of aberrant B cell-intrinsic RANK signaling remain unknown. We generated mice that express a human lymphoma-derived, hyperactive RANKK240E variant in B lymphocytes in vivo. Forced RANK signaling disrupted B cell tolerance and induced a fully penetrant systemic lupus erythematosus-like disease in addition to the development of chronic lymphocytic leukemia (CLL). Importantly, RANKK240E transgenic CLL cells as well as CLL cells of independent murine and of human origin depend on microenvironmental RANK ligand (RANKL) for tumor cell survival. Consequently, inhibition of the RANKL-RANK axis with anti-RANKL antibodies killed murine and human CLL cells in vitro and in vivo. These results establish pathological B cell-intrinsic RANK signaling as a potential driver of autoimmunity and B cell malignancy, and they suggest the exploitation of clinically available anti-RANKL compounds for CLL treatment

The prognostic impact of Claudin 6 in papillary renal cell carcinoma

Background: Claudins are promising biomarkers for diagnosis and prognosis or targets for treatment. They play a major role in signal transduction and are important in nearly all aspects of tumorigenesis. Claudin 6 is a member of the claudin family and is part of the tight junction molecule. It is reactivated in several cancer types and serves as prognostic marker in, for example, gastric, breast or non small cell lung cancer. The prognostic role of Claudin 6 in renal cell carcinoma (RCC), especially in papillary RCC (pRCC), is still unclear. Patients and Methods: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of Claudin 6 was determined by immunohistochemistry. Results: In total, Claudin 6 staining was positive in 55 of 240 type 1 and 30 of 128 type 2 pRCC cases. Kaplan-Meier analysis disclosed an overall survival of 84% for Claudin 6-compared to 78% for Claudin 6 + in pRCC type 1 tumors (p = 0.449, log-rank) and 68% for Claudin 6-compared to 65.4% for Claudin 6 + in pRCC type 2 tumors (p = 0.364, log-rank). Conclusion: In this study, claudin 6 expression showed no significant association regarding overall survival (OS) and therefore did not qualify as a prognostic marker in pRCC. Future studies will have to determine, whether Claudin 6 plays a prognostic role in other RCC entities. In addition, the function of Claudin 6 as a predictive marker for therapeutic approaches has to be evaluated in future studies

High proliferation rate and TNM stage but not histomorphological subtype are independent prognostic markers for overall survival in papillary renal cell carcinoma

Papillary renal cell carcinoma (PRCC) is currently divided in 2 subtypes. We reviewed a large cohort of PRCC and correlated subtype, morphological features and diagnostic marker expression with overall survival (OS) to uncover differences between the 2 subtypes. Three hundred seventy-six renal tumors initially diagnosed as PRCC with clinical and survival data were collected from the participating centers. Two hundred forty-six tumors were classified as PRCC1 (65.4%) and 130 as PRCC2 (34.6%) and graded according to the 2016 World Health Organization/Intemational Society of Urological Pathology grading system. Morphological features (abundant cytoplasm, necrosis, fibrous stroma, foamy macrophages and psammoma bodies) were noted. Immunohistochemical stains (MIB1, p53, Racemase, EMA, CK7, CK20, E-Cadherin) were performed using tissue microarrays. chi(2)-Tests, log-rank tests and uni- and multivariate Cox regression analysis were performed. Both subtypes displayed different morphological features and immunohistochemical profiles: abundant cytoplasm was more frequent in PRCC2, while foamy macrophages were more common in PRCC1. Abundant cytoplasm and presence of psammoma bodies were associated with poorer OS. PRCC1 showed more frequent CK7 expression, PRCC2 more frequent E-Cadherin, p53 and higher MIB1 expression (>15%). Expression of Racemase and CK7 was associated with better OS, while high MIB1 (>15%) was associated with poorer OS. In multivariate analysis, the only independent predictors of OS were proliferation (MIB1), tumor stage, metastasis and age at surgery. Subtype was not an independent prognostic factor. Therefore, PRCC subtype on its own is not suitable for estimating survival. More data focusing on PRCC tumor biology is needed to define prognostic subgroups, especially in PRCC2. (C) 2018 Elsevier Inc. All rights reserved

Characterization of PD-1 and PD-L1 Expression in Papillary Renal Cell Carcinoma: Results of a Large Multicenter Study

Understanding the impact of programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) expression becomes increasingly important in renal cell carcinoma (RCC) owing to increasing therapeutic implications. However, little is known in non -clear-cell RCC about the relevance of those immune checkpoint surrogates. Here, we suggest that PD-1/PD-L1 expression in papillary RCC does not have prognostic impact, neither for type 1 nor type 2. However, in advanced disease, further evaluation according to PD-1/PD-L1 is warranted. Background: Programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) play a decisive role as prognostic markers in clear-cell renal cell carcinoma (RCC). To date, the role of PD-1/PD-L1 as a prognostic marker in papillary RCC (pRCC) remains scarce. Patients and Methods: Patients' sample collection was a joint collaboration of the nationwide PANZAR consortium -a multicenter study. Medical history and tumor specimens were collected from 245 and 129 patients with pRCC types 1 and 2, respectively. Expression of PD-1 and PD-L1 was determined by immunohistochemistry in pRCC and tumor-infiltrating mononuclear cells. Results: Of 374 pRCC specimens, 204 type 1 and 97 type 2 were evaluable for PD-1 and PD-L1 expression analysis. In total, PD-1 and PD-L1 expression were found in 8 (4.9%) of 162 and 12 (7.2%) of 166 evaluable pRCC type 1 specimens. Comparably, PD-1 and PD-L1 expression were found in 2 (2.4%) of 83 and 5 (6.2%) of 81 evaluable pRCC type 2 specimens. Hardly any clinically relevant associations between PD-1 and PD-L1 positivity and clinicopathologic or clinical courses were observed, neither in pRCC type 1 nor type 2. Conclusion: The analysis of a large pRCC cohort from a multicenter consortium revealed no impact of PD-1/PD-L1 expression on prognosis in patients with pRCC with predominantly limited disease status, neither for type 1 nor type 2. However, the impact of PD-1 and PD-L1 in more advanced pRCC disease needs further elucidation

The Prognostic Impact of PD-L2 in Papillary Renal-Cell Carcinoma

Introduction: Programmed death-1 ligand (PD-L1) has been often studied in different types of renal-cell carcinoma (RCC). For example, in clear-cell renal carcinoma it is well established that programmed death-1 receptor and PD-L1 are important prognostic markers. In contrast, the role of programmed death-2 ligand (PD-L2) as prognostic marker remains unclear. The aim of this study was to evaluate if PD-L2 expression could play a role as a prognostic marker for papillary RCC (pRCC). Methods: The patients' sample collection was a joint collaboration of the PANZAR consortium. Patients' medical history and tumor specimens were collected from n = 240 and n = 128 patients with type 1 and 2 pRCC, respectively. Expression of PD-L2 was determined by immunohistochemistry. In total, PD-L2 staining was evaluable in 185 of 240 type 1 and 99 of 128 type 2 pRCC cases. Results: PD-L2 staining was positive in 67 (36.2%) of type 1 and in 31 (31.3%) of type 2 pRCC specimens. The prevalence of PD-L2+ cells was significantly higher in high-grade type 1 tumors (p = 0.019) and in type 2 patients with metastasis (p = 0.002). Kaplan-Meier analysis disclosed significant differences in 5-year overall survival (OS) for patients with PD-L2- compared to PD-L2+ in pRCC type 1 of 88.4% compared to 73.6% (p = 0.039) and type 2 of 78.8% compared to 39.1% % (p < 0.001). However, multivariate analysis did not identify the presence of PD-L2+ cells neither in type 1 nor type 2 pRCC as an independent predictor of poor OS. Discussion/Conclusion: PD-L2 expression did not qualify as an independent prognostic marker in pRCC. Future studies will have to determine whether anti-PD-L2-targeted treatment may play a role in pRCC and expression can potentially serve as a predictive marker for these therapeutic approaches

cMET: a prognostic marker in papillary renal cell carcinoma?

The tyrosine-protein kinase c-Met plays a decisive role in numerous cellular processes, as a proto-oncogene that supports aggressive tumor behavior. It is still unknown whether c-Met could be relevant for prognosis of papillary RCC (pRCC). Specimen collection was a collaboration of the PAN-ZAR consortium. Patients' medical history and tumor specimens were collected from 197 and 110 patients with type 1 and 2 pRCC, respectively. Expression of cMET was determined by immunohistochemistry. In total, cMET staining was evaluable in of 97 of 197 type 1 and 63 of 110 type 2 pRCC cases. Five-year overall survival revealed no significant difference in dependence of cMET positivity (cMET(-) vs. cMET(+): pRCC type 1: 84.8% vs. 80.3%, respectively [p = 0.303, log-rank]; type 2: 71.4% vs. 64.4%, respectively [p = 0.239, log-rank]). Interestingly, the subgroup analyses showed a significant difference for cMET expression in T stage and metastases of the pRCC type 2 (p = 0.014, p = 0.022, chi-square). The cMET-positive type 2 collective developed more metastases than the cMET-negative cohort (pRCC type 2 M+: cMET 2 [4.3%] vs. cMET(+): 12 [19%]). cMET expression did not qualify as a prognostic marker in pRCC for overall survival. (C) 2021 Elsevier Inc. All rights reserved

Expression of nectin-4 in papillary renal cell carcinoma

Background Nectin-4 contributes to tumor proliferation, lymphangiogenesis and angiogenesis in malignant tumors and is an emerging target in tumor therapy. In renal cell carcinoma (RCC) VEGF-directed tyrosine kinase inhibitors and checkpoint inhibitors are currently treatments of choice. Enfortumab vedotin-ejf (EV) is an antibody drug conjugate that targets Nectin-4. The aim of our study was to investigate the expression of Nectin-4 in a large cohort of papillary RCC specimens. Patients and methods Specimens were derived from the PANZAR consortium (Erlangen, Heidelberg, Herne, Homburg, Mainz, Mannheim, Marburg, Muenster, LMU Munich, TU Munich, and Regensburg). Clinical data and tissue samples from n = 190 and n = 107 patients with type 1 and 2 pRCC, respectively, were available. Expression of Nectin-4 was determined by immunohistochemistry (IHC). Results In total, Nectin-4 staining was moderately or strongly positive in of 92 (48.4%) of type 1 and 39 (36.4%) type 2 of pRCC cases. No associations between Nectin-4 expression and age at diagnosis, gender, grading, and TNM stage was found. 5 year overall survival rate was not statistically different in patients with Nectin-4 negative versus Nectin-4 positive tumors for the overall cohort and the pRCC type 2 subgroup, but higher in patient with Nectin-4 positive pRCC type 1 tumors compared to Nectin-4 negative tumors (81.3% vs. 67.8%, p = 0.042). Conclusion Nectin-4 could not be confirmed as a prognostic marker in pRCC in general. Due to its high abundance on pRCC specimens Nectin-4 is an interesting target for therapeutical approaches e.g. with EV. Clinical trials are warranted to elucidate its role in the pRCC treatment landscape

Expression of Prostate-specific Membrane Antigen (PSMA) in Papillary Renal Cell Carcinoma - Overview and Report on a Large Multicenter Cohort

Prostate specific membrane antigen (PSMA) is an emerging diagnostic and therapeutic target in prostate cancer. 68 Ga-PSMA-labeled hybrid imaging is used for the detection of prostate primary tumors and metastases. Therapeutic applications such as Lutetium-177 PSMA radionuclide therapy or bispecific antibodies that target PSMA are currently under investigation within clinical trials. The expression of PSMA, however, is not specific to prostate-tissue. It has been described in the neovascular endothelium of different types of cancer such as breast cancer, and clear cell renal cell carcinoma (ccRCC). The aim of this study was to analyze PSMA expression in papillary RCC (pRCC) type 1 and type 2, the most common non-ccRCC subtypes, and to evaluate the potential of PSMA-targeted imaging and treatment in pRCC. Formalin-fixed, paraffin-embedded tissue samples of primary tumors were analyzed for PSMA expression by immunohistochemistry. Out of n=374 pRCC specimens from the multicenter PANZAR consortium, n=197 pRCC type 1 and n=110 type 2 specimens were eligible for analysis and correlated with clinical data. In pRCC type 1 PSMA staining was positive in 4 of 197 (2.0%) samples whereas none (0/110) of the pRCC type 2 samples were positive for PSMA in this large cohort of pRCC patients. No significant PSMA expression was detected in pRCC. Reflecting current clinical evaluation of PMSA expression in RCC do not encourage further analysis in papillary subtypes