. 2021 Mar; 12:653358.
doi: 10.3389/fimmu.2021.653358.

Roles of the Dynamic Tumor Immune Microenvironment in the Individualized Treatment of Advanced Clear Cell Renal Cell Carcinoma

Enyu Lin 1 Xuechao Liu 2 Yanjun Liu 3 Zedan Zhang 1 Lu Xie 1 Kaiwen Tian 1 Jiumin Liu 1 Yuming Yu 1 
  • PMID: 33746989
  •     174 References
  •     1 citations


Immune checkpoint inhibitors (ICIs) are currently a first-line treatment option for clear cell renal cell carcinoma (ccRCC). However, recent clinical studies have shown that a large number of patients do not respond to ICIs. Moreover, only a few patients achieve a stable and durable response even with combination therapy based on ICIs. Available studies have concluded that the response to immunotherapy and targeted therapy in patients with ccRCC is affected by the tumor immune microenvironment (TIME), which can be manipulated by targeted therapy and tumor genomic characteristics. Therefore, an in-depth understanding of the dynamic nature of the TIME is important for improving the efficacy of immunotherapy or combination therapy in patients with advanced ccRCC. Here, we explore the possible mechanisms by which the TIME affects the efficacy of immunotherapy and targeted therapy, as well as the factors that drive dynamic changes in the TIME in ccRCC, including the immunomodulatory effect of targeted therapy and genomic changes. We also describe the progress on novel therapeutic modalities for advanced ccRCC based on the TIME. Overall, this review provides valuable information on the optimization of combination therapy and development of individualized therapy for advanced ccRCC.

Keywords: clear cell renal cell carcinoma; genomic characteristics; immunotherapy; targeted therapy; tumor immune microenvironment.

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A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice.
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Cytokine, 2019 Feb 21; 117. PMID: 30784898
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Knockdown of VEGF receptor-1 (VEGFR-1) impairs macrophage infiltration, angiogenesis and growth of clear cell renal cell carcinoma (CRCC).
Chenghai Li, Bin Liu, Zonghan Dai, Yunxia Tao.
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Molecular subtypes of clear cell renal cell carcinoma are associated with sunitinib response in the metastatic setting.
Benoit Beuselinck, Sylvie Job, +16 authors, Jessica Zucman-Rossi.
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Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma.
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Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors.
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The Association Between PD-L1 Expression and the Clinical Outcomes to Vascular Endothelial Growth Factor-Targeted Therapy in Patients With Metastatic Clear Cell Renal Cell Carcinoma.
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Human renal cell carcinoma induces a dendritic cell subset that uses T-cell crosstalk for tumor-permissive milieu alterations.
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Interleukin-2: Old and New Approaches to Enhance Immune-Therapeutic Efficacy.
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Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
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Semin Cancer Biol, 2017 Dec 13; 52(Pt 2). PMID: 29229461
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The mTOR signalling pathway in human cancer.
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Heather J Dalton, Sunila Pradeep, +22 authors, Anil K Sood.
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The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy.
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Impact of immune parameters on long-term survival in metastatic renal cell carcinoma.
Frede Donskov, Hans von der Maase.
J Clin Oncol, 2006 May 02; 24(13). PMID: 16648500
Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer.
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N Engl J Med, 2018 Apr 17; 378(22). PMID: 29658856
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The Immunobiology of Kidney Cancer.
Charles G Drake, Mark N Stein.
J Clin Oncol, 2018 Oct 30;. PMID: 30372396
Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression.
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Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma.
Suzanne George, Diana Miao, +13 authors, Eliezer M Van Allen.
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Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines.
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Svenja Bihr, Riuko Ohashi, +9 authors, Peter Schraml.
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SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.
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Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma.
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Loss of PTEN Promotes Resistance to T Cell-Mediated Immunotherapy.
Weiyi Peng, Jie Qing Chen, +41 authors, Patrick Hwu.
Cancer Discov, 2015 Dec 10; 6(2). PMID: 26645196    Free PMC article.
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Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
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Cancer Immunol Immunother, 2006 Sep 09; 56(5). PMID: 16960692
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Pegilodecakin as monotherapy or in combination with anti-PD-1 or tyrosine kinase inhibitor in heavily pretreated patients with advanced renal cell carcinoma: Final results of cohorts A, G, H and I of IVY Phase I study.
Nizar M Tannir, Kyriakos P Papadopoulos, +8 authors, Aung Naing.
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Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism.
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Chemokines and chemokine receptors: an overview.
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Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.
Dan Huang, Yan Ding, +7 authors, Bin Tean Teh.
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Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers.
Vincent Alcazer, Paola Bonaventura, Stephane Depil.
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Cancer immunotherapy using checkpoint blockade.
Antoni Ribas, Jedd D Wolchok.
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Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
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Inferring tumour purity and stromal and immune cell admixture from expression data.
Kosuke Yoshihara, Maria Shahmoradgoli, +12 authors, Roel G W Verhaak.
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NCCN Guidelines Insights: Kidney Cancer, Version 2.2020.
Robert J Motzer, Eric Jonasch, +33 authors, Griselda Zuccarino-Catania.
J Natl Compr Canc Netw, 2019 Nov 07; 17(11). PMID: 31693980
Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures.
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Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma.
Lucía Carril-Ajuria, María Santos, +2 authors, Guillermo de Velasco.
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The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial.
Charlotte M Huijts, Sinéad M Lougheed, +8 authors, Dutch WIN-O Consortium.
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Highly Cited. Review.
Resistance to PD1/PDL1 checkpoint inhibition.
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Tim-3 and its role in regulating anti-tumor immunity.
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Pancreatic tropism of metastatic renal cell carcinoma.
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Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.
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Interleukin-6 induces drug resistance in renal cell carcinoma.
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VEGF and FGF-2: Promising targets for the treatment of respiratory disorders.
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Iñigo Terrén, Ane Orrantia, +2 authors, Francisco Borrego.
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Prognostic Relevance of ZNF844 and Chr 19p13.2 KRAB-Zinc Finger Proteins in Clear Cell Renal Carcinoma.
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