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    Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma. Clark David J,Dhanasekaran Saravana M,Petralia Francesca,Pan Jianbo,Song Xiaoyu,Hu Yingwei,da Veiga Leprevost Felipe,Reva Boris,Lih Tung-Shing M,Chang Hui-Yin,Ma Weiping,Huang Chen,Ricketts Christopher J,Chen Lijun,Krek Azra,Li Yize,Rykunov Dmitry,Li Qing Kay,Chen Lin S,Ozbek Umut,Vasaikar Suhas,Wu Yige,Yoo Seungyeul,Chowdhury Shrabanti,Wyczalkowski Matthew A,Ji Jiayi,Schnaubelt Michael,Kong Andy,Sethuraman Sunantha,Avtonomov Dmitry M,Ao Minghui,Colaprico Antonio,Cao Song,Cho Kyung-Cho,Kalayci Selim,Ma Shiyong,Liu Wenke,Ruggles Kelly,Calinawan Anna,Gümüş Zeynep H,Geiszler Daniel,Kawaler Emily,Teo Guo Ci,Wen Bo,Zhang Yuping,Keegan Sarah,Li Kai,Chen Feng,Edwards Nathan,Pierorazio Phillip M,Chen Xi Steven,Pavlovich Christian P,Hakimi A Ari,Brominski Gabriel,Hsieh James J,Antczak Andrzej,Omelchenko Tatiana,Lubinski Jan,Wiznerowicz Maciej,Linehan W Marston,Kinsinger Christopher R,Thiagarajan Mathangi,Boja Emily S,Mesri Mehdi,Hiltke Tara,Robles Ana I,Rodriguez Henry,Qian Jiang,Fenyö David,Zhang Bing,Ding Li,Schadt Eric,Chinnaiyan Arul M,Zhang Zhen,Omenn Gilbert S,Cieslik Marcin,Chan Daniel W,Nesvizhskii Alexey I,Wang Pei,Zhang Hui, Cell To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology. 10.1016/j.cell.2019.10.007
    Identification and validation of dichotomous immune subtypes based on intratumoral immune cells infiltration in clear cell renal cell carcinoma patients. Xiong Ying,Wang Zewei,Zhou Quan,Zeng Han,Zhang Hongyu,Liu Zhaopei,Huang Qiuren,Wang Jiajun,Chang Yuan,Xia Yu,Wang Yiwei,Liu Li,Zhu Yu,Xu Le,Dai Bo,Bai Qi,Guo Jianming,Xu Jiejie Journal for immunotherapy of cancer BACKGROUND:Increasing evidence has elucidated the clinical significance of tumor infiltrating immune cells in predicting outcomes and therapeutic efficacy. In this study, we comprehensively analyze the tumor microenvironment (TME) immune cell infiltrations in clear cell renal cell carcinoma (ccRCC) and correlated the infiltration patterns with anti-tumor immunity and clinical outcomes. METHODS:We analyzed immune cell infiltrations in four independent cohorts, including the KIRC cohort of 533 patients, the Zhongshan ccRCC cohorts of 259 patients, the Zhongshan fresh tumor sample cohorts of 20 patients and the Zhongshan metastatic ccRCC cohorts of 87 patients. Intrinsic patterns of immune cell infiltrations were evaluated for associations with clinicopathological characteristics, underlying biological pathways, genetic changes, oncological outcomes and treatment responses. RESULTS:Unsupervised clustering of tumor infiltrating immune cells identified two microenvironment subtypes, TMEcluster-A and TMEcluster-B. Gene markers and biological pathways referring to immune evasion were upregulated in TMEcluster-B. TMEcluster-B associated with poor overall survival (p<0.001; HR 2.629) and recurrence free survival (p=0.012; HR 1.870) in ccRCC validation cohort. TMEcluster-B cases had worse treatment response (p=0.009), overall survival (p<0.001; HR 2.223) and progression free survival (p=0.015; HR 2.7762) in metastatic ccRCC cohort. The predictive accuracy of International Metastatic Database Consortium risk score was improved after incorporation of TME clusters. CONCLUSIONS:TMEcluster-A featured increased mast cells infiltration, prolonged survival and better treatment response. TMEcluster-B was a heavily infiltrated but immunosuppressed phenotype enriched for macrophages, CD4 T cells, Tregs, CD8 T cells and B cells. TMEcluster-B predicted dismal survival and worse treatment response in clear cell renal cell carcinoma patients. 10.1136/jitc-2019-000447
    Tumor Microenvironment Features as Predictive Biomarkers of Response to Immune Checkpoint Inhibitors (ICI) in Metastatic Clear Cell Renal Cell Carcinoma (mccRCC). Simonaggio Audrey,Epaillard Nicolas,Pobel Cédric,Moreira Marco,Oudard Stéphane,Vano Yann-Alexandre Cancers Renal cell carcinoma (RCC) is the seventh most frequently diagnosed malignancy with an increasing incidence in developed countries. Despite a greater understanding of the cancer biology, which has led to an increase of therapeutic options, metastatic clear cell renal cell carcinoma (mccRCC) still have a poor prognosis with a median five-years survival rate lower than 10%. The standard of care for mccRCC has changed dramatically over the past decades with the emergence of new treatments: anti-VEGFR tyrosine kinase inhibitors, mTOR Inhibitors and immune checkpoint inhibitors (ICI) such as anti-Programmed cell-Death 1 (PD-1) and anti-anti-Programmed Death Ligand-1 (PD-L1) used as monotherapy or as a combination with anti CTLA-4 or anti angiogenic therapies. In the face of these rising therapeutic options, the question of the therapeutic sequences is crucial. Predictive biomarkers are urgently required to provide a personalized treatment for each patient. Disappointingly, the usual ICI biomarkers, PD-L1 expression and Tumor Mutational Burden, approved in melanoma or non-small cell lung cancer (NSCLC) have failed to distinguish good and poor mccRCC responders to ICI. The tumor microenvironment is known to be involved in ICI response. Innovative technologies can be used to explore the immune contexture of tumors and to find predictive and prognostic biomarkers. Recent comprehensive molecular characterization of RCC has led to the development of robust genomic signatures, which could be used as predictive biomarkers. This review will provide an overview of the components of the RCC tumor microenvironment and discuss their role in disease progression and resistance to ICI. We will then highlight the current and future ICI predictive biomarkers assessed in mccRCC with a major focus on immunohistochemistry markers and genomic signatures. 10.3390/cancers13020231
    Progress and Challenges in Precise Treatment of Tumors With PD-1/PD-L1 Blockade. Jiang Youhai,Zhao Xiaofang,Fu Jing,Wang Hongyang Frontiers in immunology Immune checkpoint inhibitors target the inhibitory receptors on T cells to reinstate their antitumor ability and have shown significant efficacy in treating various cancers. However, because of tumor heterogeneity and many other uncover reasons, the objective response rate for programmed death 1 and programmed death-ligand 1 (PD-1/PD-L1) blockade is only 20 to 30%; its response rate in solid tumors is relatively low, and different degrees of side effects have occurred. There are still many unknown factors affecting the therapeutic effectiveness of PD-1/PD-L1 blockade. Additionally, screening the responding tumor patients accurately and improving the response rate and efficacy are huge challenges for tumor precise treatment. Here, we attempt to summarize the recent progress in response prediction and combined application of PD-1/PD-L1 blockade and briefly discuss the methods and evaluations combined with PD-1/PD-L1 blockade to improve the implementation of precision immunotherapy. 10.3389/fimmu.2020.00339
    Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response. Proceedings of the National Academy of Sciences of the United States of America Diverse subtypes of renal cell carcinomas (RCCs) display a wide spectrum of histomorphologies, proteogenomic alterations, immune cell infiltration patterns, and clinical behavior. Delineating the cells of origin for different RCC subtypes will provide mechanistic insights into their diverse pathobiology. Here, we employed single-cell RNA sequencing (scRNA-seq) to develop benign and malignant renal cell atlases. Using a random forest model trained on this cell atlas, we predicted the putative cell of origin for more than 10 RCC subtypes. scRNA-seq also revealed several attributes of the tumor microenvironment in the most common subtype of kidney cancer, clear cell RCC (ccRCC). We elucidated an active role for tumor epithelia in promoting immune cell infiltration, potentially explaining why ccRCC responds to immune checkpoint inhibitors, despite having a low neoantigen burden. In addition, we characterized an association between high endothelial cell types and lack of response to immunotherapy in ccRCC. Taken together, these single-cell analyses of benign kidney and RCC provide insight into the putative cell of origin for RCC subtypes and highlight the important role of the tumor microenvironment in influencing ccRCC biology and response to therapy. 10.1073/pnas.2103240118
    Determination of the Expression of PD-L1 in the Morphologic Spectrum of Renal Cell Carcinoma. Walter Beatriz,Gil Sara,Naizhen Xu,Kruhlak Michael J,Linehan W Marston,Srinivasan Ramaprasad,Merino Maria J Journal of Cancer Immunotherapy is reportedly an effective form of therapy for some advanced cancers such as lung adenocarcinoma, malignant melanoma and colorectal adenocarcinoma. In renal cell carcinoma (RCC), the role of immunotherapy is under investigation. Programmed Death-Ligand 1 (PD-L1) is a molecule expressed on the surface of certain tumor cells and binds to the Programmed cell death protein 1 (PD-1) on cytotoxic T-cells, an interaction that inhibits the antitumor immune response. The aim of this study is to evaluate PD-L1 expression in the morphologic spectrum of RCC. A total of 172 cases of RCC comprising all types were studied and the PD-L1 was correlated with immune response for CD4 and CD8. Positive membranous staining for PD-L1 was seen in 59 (34%) of the 172 samples. The positive cases were HLRCC (31/53), Type 1 Papillary RCC (10/31), Chromophobe (7/20), Hybrid (3/9), TFE-3 related cancer (3/8), Undifferentiated (3/5), and TFEB tumors (2/2). Clear cell carcinomas, Oncocytomas and SDHB deficient-RCC didn't show any expression of PD-L1; (0/34;0/7;0/3). Our results demonstrated that aggressive forms of RCC such as HLRCC have high expression of PD-L1, in contrast to clear cell renal carcinomas. Our findings support a possible role of anti-PD-L1/PD-1 immunotherapies in the treatment of PD-L1-positive RCC. 10.7150/jca.35738