Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

Argentiero, Antonella; Solimando, Antonio Giovanni; Krebs, Markus; Leone, Patrizia; Susca, Nicola; Brunetti, Oronzo; Racanelli, Vito; Vacca, Angelo; Silvestris, Nicola

doi:10.20944/preprints202004.0181.v1

Cited by 28 publications

(21 citation statements)

References 93 publications

(131 reference statements)

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“…In 2020, there are more than 431,000 new cases and 179,000 deaths from kidney cancer in the world [3]. Kidney renal clear cell carcinoma (KIRC), the most common histological subtype, is characterized by extensive tumor heterogeneity, distinct clinical courses, and potential specific treatment vulnerabilities [4]. Genetic alterations occur frequently in KIRC, such as somatic mutations of VHL, PBRM1, SETD2, BAP1, KDM5C,…”

Section: Introductionmentioning

confidence: 99%

A Novel Prognostic Predictor of Immune Microenvironment and Therapeutic Response in Kidney Renal Clear Cell Carcinoma based on Necroptosis-related Gene Signature

Chen¹,

Lin²,

Wu³

et al. 2022

Int. J. Med. Sci.

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Background: Necroptosis, a cell death of caspase-independence, plays a pivotal role in cancer biological regulation. Although necroptosis is closely associated with oncogenesis, cancer metastasis, and immunity, there remains a lack of studies determining the role of necroptosis-related genes (NRGs) in the highly immunogenic cancer type, kidney renal clear cell carcinoma (KIRC). Methods: The information of clinicopathology and transcriptome was extracted from TCGA database. Following the division into the train and test cohorts, a three-NRGs (TLR3, FASLG, ZBP1) risk model was identified in train cohort by LASSO regression. The overall survival (OS) comparison was conducted between different risk groups through Kaplan-Meier analysis, which was further validated in test cohort. The Cox proportional hazards regression model was introduced to assess its impact of clinicopathological factors and risk score on survival. ESTIMATE and CIBERSORT algorithms were introduced to evaluate immune microenvironment, while enrichment analysis was conducted to explore the biological significance. Correlation analysis was applied for the correlation assessment between checkpoint gene expression and risk score, between gene expression and therapeutic response. Gene expressions from TCGA were verified by GEO datasets and immunohistochemistry (IHC) analysis. Results: This NRGs-related signature predicted poorer OS in high-risk group, which was also verified in test cohort. Risk score could also independently predict survival outcome of KIRC. Significant changes were also found in immune microenvironment and checkpoint gene expressions between different risk groups, with immune functional enrichment in high-risk group. Interestingly, therapeutic response was correlated with the expressions of NRGs. The expressions of NRGs from TCGA were consistent with those from GEO datasets and IHC analysis. Conclusion:The NRGs-related signature functions as a novel prognostic predictor of immune microenvironment and therapeutic response in KIRC.

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Section: Introductionmentioning

confidence: 99%

A Novel Prognostic Predictor of Immune Microenvironment and Therapeutic Response in Kidney Renal Clear Cell Carcinoma based on Necroptosis-related Gene Signature

Chen¹,

Lin²,

Wu³

et al. 2022

Int. J. Med. Sci.

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“…e results from drug sensitivity analysis revealed that low PIK3CA is resistant to 19 small molecules or drugs, demonstrating that PIK3CA is a promising biomarker for drug screening. Indeed, a decision-making strategy based on clinicalhistopathological criteria had been developed for renal cell carcinoma, and we could predict the prognosis of patients based on the subtype so that different drugs or treatment regimens can be selected for therapy, reducing treatmentrelated complications [6]. We should identify more reliable predictive biomarkers of treatment individual sensitivity or resistance, thus prompting precise and individualized treatment.…”

Section: Discussionmentioning

confidence: 99%

“…e pathogenesis of KIRC is extremely complex, involving multiple genes at multiple steps. Moreover, there are no credible predictive markers for the prognosis and treatment of individual sensitivity or resistance in renal cell carcinoma, though some prognostic factors associated with the survival of RCC patients have been described [6,7]. Hence, the identification of new drug targets for KIRC by exploring gene networks for changes associated with tumorigenesis and progression has become the focus of numerous studies.…”

Section: Introductionmentioning

confidence: 99%

Identification and Validation of PIK3CA as a Marker Associated with Prognosis and Immune Infiltration in Renal Clear Cell Carcinoma

Wang

Gao

et al. 2021

Journal of Oncology

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Background. Kidney renal clear cell carcinoma (KIRC) is the most prevalent renal malignancy. The therapeutic strategies for advanced KIRC are very few, with only sunitinib being widely approved. Mutations in the PIK3CA gene can affect tumor cell proliferation, metastasis, and patients’ survival. Methods. Bioinformatics analysis was performed to explore the expression and clinical significance of PIK3CA in KIRC. Moreover, qRT-PCR was conducted to verify the result. Results. Subgroup analyses of KIRC tissue based on gender, tumor grade, and cancer stage indicated downregulation of PIK3CA mRNA expression. The KIRC patients with high PIK3CA expression indicated a better overall survival, progression-free survival, and disease-free survival. A predictive nomogram was constructed and demonstrated that the calibration plots for the 3-year and 5-year OS rates were predicted relatively well compared with an ideal model in the TCGA KIRC cohort. The validation study revealed that downregulation of PIK3CA in KIRC tissues and low PIK3CA expression had a poor overall survival with an AUC of 0.775 in the ROC curve. Moreover, Cox regression analysis revealed that PIK3CA expression and clinical stage were independent factors affecting the prognosis of KIRC patients. PIK3CA expression was found to be significantly associated with the abundance of immune cells and immune biomarker sets. PIK3CA and associated genes were found to be mainly associated with immune response and the JAK-STAT signaling pathway. Conclusion. We identified PIK3CA as a potential biomarker for prognosis correlated with immune infiltrates in KIRC. Further studies should focus on the functions of PIK3CA in KIRC carcinogenesis.

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“…Conversely, the combination of nivolumab + ipilimumab in the CheckMate-214 study showed a 42% ORR compared to 26% in the sunitinib arm. In the same study, the immunotherapy combination obtained a median OS gain of 20 months compared to the sunitinib arm (47 versus 26.6 months, respectively) ( 58 ).…”

Section: Introductionmentioning

confidence: 95%

“…Both studies highlighted a difference between the IMDC prognostic groups, showing that the intermediate- and high-risk groups tended to benefit more from immunotherapy, contrary to what happens in good prognosis cases, which appear to do better with oral TKIs ( 58 ). Recently, McDermott et al evaluated the impact of immunotherapy according to the IMDC risk criteria, selecting a heatmap of genes previously established as angiogenesis-related and immune biology-related genes.…”

Section: Introductionmentioning

confidence: 99%

Potential Application of Chimeric Antigen Receptor (CAR)-T Cell Therapy in Renal Cell Tumors

et al. 2020

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Currently, renal cell carcinoma is characterized by encouraging benefits from immunotherapy that have led to significant results in treatment outcome. The approval of nivolumab primarily as second-line monotherapy and, more recently, the approval of new combination therapies as first-line treatment have confirmed the importance of immunotherapy in this type of tumor. In this context, the chimeric antigen receptor (CAR)-T represents a further step forward in the field of immunotherapy. Initially tested on hematological malignancies, this new therapeutic approach is also becoming a topic of great interest for solid tumors. Although the treatment has several advantages over previous T-cell receptor-dependent immunotherapy, it is facing some obstacles in solid tumors such as a hostile tumor microenvironment and on-tumor/off-tumor toxicities. Several strategies are under investigation to overcome these problems, but the approval of CART cell therapy is still some way off. In renal cancer, the significant advantages obtained from immune checkpoint inhibitors represent a good starting point, but the potential nephrological toxicity of CART cell therapy represents an important risk. In this review, we provide the rationale and preliminary results of CART cell therapy in renal cell malignancies.

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Anti-Angiogenesis and Immunotherapy: Novel Paradigms to Envision Tailored Approaches in Renal Cell-Carcinoma

Cited by 28 publications

References 93 publications

A Novel Prognostic Predictor of Immune Microenvironment and Therapeutic Response in Kidney Renal Clear Cell Carcinoma based on Necroptosis-related Gene Signature

A Novel Prognostic Predictor of Immune Microenvironment and Therapeutic Response in Kidney Renal Clear Cell Carcinoma based on Necroptosis-related Gene Signature

Identification and Validation of PIK3CA as a Marker Associated with Prognosis and Immune Infiltration in Renal Clear Cell Carcinoma

Potential Application of Chimeric Antigen Receptor (CAR)-T Cell Therapy in Renal Cell Tumors

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