Abstract 2742: Integrated multiregional transcriptomic and multi-parameter single-cell imaging analysis of clear cell renal cell carcinoma elucidates diverse cellular communities present within the tumor microenvironment

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.

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MP39-12 HIGHER SERUM C-REACTIVE PROTEIN LEVEL REPRESENTS THE IMMUNOSUPPRESSIVE TUMOR MICROENVIRONMENT IN PATIENTS WITH CLEAR CELL RENAL CELL CARCINOMA

The Journal of Urology ◽

10.1016/j.juro.2017.02.1186 ◽

2017 ◽

Vol 197 (4S) ◽

Author(s):

Takayuki Nakayama ◽

Kazutaka Saito ◽

Yuma Waseda ◽

Hajime Tanaka ◽

Masaharu Inoue ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Microenvironment ◽

Cell Carcinoma ◽

Protein Level ◽

Renal Cell ◽

Clear Cell ◽

C Reactive Protein ◽

Cell Renal Cell Carcinoma ◽

Reactive Protein ◽

Immunosuppressive Tumor Microenvironment

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Identification of a Six-Gene Prognostic Signature Characterized by Tumor Microenvironment Immune Profiles in Clear Cell Renal Cell Carcinoma

Frontiers in Genetics ◽

10.3389/fgene.2021.722421 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lu Zhang ◽

Jianlong Li ◽

Mengzhao Zhang ◽

Lu Wang ◽

Tao Yang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Microenvironment ◽

Risk Stratification ◽

Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Prognostic Signature ◽

Characteristic Analysis ◽

Cell Renal Cell Carcinoma ◽

Cox Regression Analysis

Clear cell renal cell carcinoma (ccRCC) is widely acknowledged to be extremely sensitive to immunotherapy, emphasizing the tremendous impacts on which the tumor microenvironment (TME) has shown. However, the molecular subgroups characterized by the TME features scarcely serve as the risk stratification guides in clinical practice for survival outcomes and immunotherapy response prediction. This study generated fresh insights into a novel TME-related prognostic signature derived from The Cancer Genome Atlas database using integrated bioinformatics analyses. Subsequently, Kaplan–Meier survival analysis, receiver operating characteristic analysis, and univariate and multivariate Cox regression analysis were performed to evaluate and validate the efficacy and the accuracy of the signature in ccRCC prognosis. Furthermore, we discovered that the risk score presented an increased likelihood of correlation with miscellaneous clinicopathological characteristics, natural killer cell-mediated cytotoxicity, immune cell infiltration levels, and immune checkpoint expression. These findings highlighted the notion that the six-gene signature characterized by the TME features may have implications on the risk stratification for personalized and precise immunotherapeutic management.

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Tumor Microenvironment-responsive Nanodrug for Clear-cell Renal Cell Carcinoma Therapy via Triggering Waterfall-like Cascade Ferroptosis

10.21203/rs.3.rs-842110/v1 ◽

2021 ◽

Author(s):

Wenjun Ni ◽

Yongxiang Li ◽

Lingxia Liang ◽

Cuixia Lu ◽

Meixiao Zhan ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Tumor Microenvironment ◽

Cell Carcinoma ◽

Targeted Delivery ◽

Renal Cell ◽

Water Solubility ◽

Clear Cell ◽

Iron Ions ◽

Ferrous Ions ◽

Cell Renal Cell Carcinoma

Abstract BackgroundThe most common type of kidney tumor, clear-cell renal cell carcinoma (ccRCC) with relatively insidious development and easily metastatic characteristics is generally insensitive to cytotoxic chemotherapy. Advanced ccRCC lacks effective treatment and has a poor prognosis. Fortunately, ccRCC with the hallmark of abundant polyunsaturated fatty acids (PUFAs) content is regarded as intrinsically vulnerable to ferroptosis-based therapeutic strategies. Nonetheless, the classic ferroptosis agonist (RSL3) with low specificity for tumors, short half-life in the blood, poor water solubility and deficient accumulation at the tumor site prevents its reliable application in vivo. ResultsIn this study, iron-based metal-organic framework nanoparticles (MIL-101(Fe) NPs) delivered RSL3 to ccRCC tumors, and then released the iron ions and RSL3 accompanied by the degradation of MIL-101(Fe) NPs in the acidic tumor microenvironment. The MIL-101(Fe)@RSL3 as a pH-responsive nanodrug causes cellular iron overload and promotes the hydroxyl radical (•OH) generation by Fenton reaction to attack PUFAs, leading to the aberrant accumulation of lipid peroxides (L-OOH). Additionally, RSL3 directly inhibits glutathione peroxidase 4 (GPX4) to detoxify L-OOH, and ferrous ions further catalyze the irreversible conversion of highly reactive lipid alkoxyl radicals (L-O•) from L-OOH to triggering waterfall-like cascade ferroptosis. In contrast to the limited antitumor efficiency of free RSL3, MIL-101(Fe)@RSL3 with high encapsulation efficiency (88.7%) shows a significant ccRCC-specific antitumor effect and negligible side effects.ConclusionMIL-101(Fe)@RSL3 could aggravate ferroptosis and be expected to be a promising nanodrug for ccRCC systemic therapy due to the targeted delivery and responsive release of RSL3 and iron ions.

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