Review
. 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 
Affiliations
  • PMID: 33746989
  •     174 References
  •     1 citations

Abstract

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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Expert Opin Drug Metab Toxicol, 2016 Jul 28; 12(9). PMID: 27450183
Review.
Regulatory T cells in cancer immunosuppression - implications for anticancer therapy.
Yosuke Togashi, Kohei Shitara, Hiroyoshi Nishikawa.
Nat Rev Clin Oncol, 2019 Feb 02; 16(6). PMID: 30705439
Highly Cited. Review.
A STING Agonist Given with OX40 Receptor and PD-L1 Modulators Primes Immunity and Reduces Tumor Growth in Tolerized Mice.
Jeremy B Foote, Marleen Kok, +7 authors, Leisha A Emens.
Cancer Immunol Res, 2017 May 10; 5(6). PMID: 28483787    Free PMC article.
Highly Cited.
Increase of circulating CD4+CD25highFoxp3+ regulatory T cells in patients with metastatic renal cell carcinoma during treatment with dendritic cell vaccination and low-dose interleukin-2.
Annika Berntsen, Marie Klinge Brimnes, Per thor Straten, Inge Marie Svane.
J Immunother, 2010 Apr 14; 33(4). PMID: 20386464
Nivolumab for Metastatic Renal Cell Carcinoma: Results of a Randomized Phase II Trial.
Robert J Motzer, Brian I Rini, +12 authors, Hans J Hammers.
J Clin Oncol, 2014 Dec 03; 33(13). PMID: 25452452    Free PMC article.
Highly Cited.
The role of cytokines in the regulation of NK cells in the tumor environment.
Gordana M Konjević, Ana M Vuletić, +2 authors, Vladimir B Jurišić.
Cytokine, 2019 Feb 21; 117. PMID: 30784898
Highly Cited. Review.
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.
Cancer Biol Ther, 2011 Oct 13; 12(10). PMID: 21989163    Free PMC article.
Overriding TKI resistance of renal cell carcinoma by combination therapy with IL-6 receptor blockade.
Kei Ishibashi, Tobias Haber, +15 authors, Yoshiyuki Kojima.
Oncotarget, 2017 Sep 15; 8(33). PMID: 28903416    Free PMC article.
Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis.
Samra Turajlic, Kevin Litchfield, +17 authors, Charles Swanton.
Lancet Oncol, 2017 Jul 12; 18(8). PMID: 28694034
Highly Cited.
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.
Clin Cancer Res, 2015 Jan 15; 21(6). PMID: 25583177
Comprehensive molecular characterization of clear cell renal cell carcinoma.
Cancer Genome Atlas Research Network.
Nature, 2013 Jun 25; 499(7456). PMID: 23792563    Free PMC article.
Highly Cited.
Targeting costimulatory molecules to improve antitumor immunity.
Daria Capece, Daniela Verzella, +2 authors, Edoardo Alesse.
J Biomed Biotechnol, 2012 Apr 14; 2012. PMID: 22500111    Free PMC article.
Review.
BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.
Karen H Ventii, Narra S Devi, +4 authors, Keith D Wilkinson.
Cancer Res, 2008 Sep 02; 68(17). PMID: 18757409    Free PMC article.
Highly Cited.
Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma.
Xian-De Liu, Anh Hoang, +20 authors, Eric Jonasch.
Cancer Immunol Res, 2015 May 28; 3(9). PMID: 26014097    Free PMC article.
Immunological effects of everolimus in patients with metastatic renal cell cancer.
Charlotte M Huijts, Saskia J Santegoets, +3 authors, Hans J van der Vliet.
Int J Immunopathol Pharmacol, 2017 Oct 11; 30(4). PMID: 28988508    Free PMC article.
Neuropilin 1 guides regulatory T cells into VEGF-producing melanoma.
Wiebke Hansen.
Oncoimmunology, 2013 Mar 26; 2(2). PMID: 23524975    Free PMC article.
Myeloid-Derived Suppressor Cells Hinder the Anti-Cancer Activity of Immune Checkpoint Inhibitors.
Rebekka Weber, Viktor Fleming, +5 authors, Viktor Umansky.
Front Immunol, 2018 Jun 27; 9. PMID: 29942309    Free PMC article.
Highly Cited. Review.
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.
Su-Jin Shin, Yoon Kyung Jeon, +4 authors, Heounjeong Go.
Oncologist, 2015 Oct 02; 20(11). PMID: 26424759    Free PMC article.
Human renal cell carcinoma induces a dendritic cell subset that uses T-cell crosstalk for tumor-permissive milieu alterations.
Ainhoa-M Figel, Dorothee Brech, +13 authors, Elfriede Noessner.
Am J Pathol, 2011 Jun 28; 179(1). PMID: 21703422    Free PMC article.
Macrophage-Mediated Subversion of Anti-Tumour Immunity.
Valeria Quaranta, Michael C Schmid.
Cells, 2019 Jul 25; 8(7). PMID: 31331034    Free PMC article.
Review.
Interleukin-2: Old and New Approaches to Enhance Immune-Therapeutic Efficacy.
Pooja Dhupkar, Nancy Gordon.
Adv Exp Med Biol, 2017 Mar 23; 995. PMID: 28321811
Review.
Targeting Tumor-Associated Macrophages as a Potential Strategy to Enhance the Response to Immune Checkpoint Inhibitors.
Luca Cassetta, Takanori Kitamura.
Front Cell Dev Biol, 2018 Apr 20; 6. PMID: 29670880    Free PMC article.
Highly Cited. Review.
Predictive markers of anti-VEGF and emerging role of angiogenesis inhibitors as immunotherapeutics.
Priti S Hegde, Jeffrey J Wallin, Christoph Mancao.
Semin Cancer Biol, 2017 Dec 13; 52(Pt 2). PMID: 29229461
Review.
The immune contexture in human tumours: impact on clinical outcome.
Wolf Herman Fridman, Franck Pagès, Catherine Sautès-Fridman, Jérôme Galon.
Nat Rev Cancer, 2012 Mar 16; 12(4). PMID: 22419253
Highly Cited. Review.
The mTOR signalling pathway in human cancer.
Helena Pópulo, José Manuel Lopes, Paula Soares.
Int J Mol Sci, 2012 Mar 13; 13(2). PMID: 22408430    Free PMC article.
Highly Cited. Review.
Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.
Robert J Motzer, Konstantin Penkov, +25 authors, Toni K Choueiri.
N Engl J Med, 2019 Feb 20; 380(12). PMID: 30779531    Free PMC article.
Highly Cited.
Macrophages Facilitate Resistance to Anti-VEGF Therapy by Altered VEGFR Expression.
Heather J Dalton, Sunila Pradeep, +22 authors, Anil K Sood.
Clin Cancer Res, 2017 Sep 01; 23(22). PMID: 28855350    Free PMC article.
MMP-9 secreted by tumor associated macrophages promoted gastric cancer metastasis through a PI3K/AKT/Snail pathway.
Lin Liu, Yu Ye, Xiumei Zhu.
Biomed Pharmacother, 2019 Jun 16; 117. PMID: 31202170
Tumor associated regulatory dendritic cells.
Yang Ma, Galina V Shurin, Dmitriy W Gutkin, Michael R Shurin.
Semin Cancer Biol, 2012 Mar 15; 22(4). PMID: 22414911    Free PMC article.
Review.

Botao Fa, Chengwen Luo, +3 authors, Zhangsheng Yu.
EBioMedicine, 2019 May 19; 44. PMID: 31101593    Free PMC article.
Clinical Validation of PBRM1 Alterations as a Marker of Immune Checkpoint Inhibitor Response in Renal Cell Carcinoma.
David A Braun, Yuko Ishii, +4 authors, Toni K Choueiri.
JAMA Oncol, 2019 Sep 06; 5(11). PMID: 31486842    Free PMC article.
Highly Cited.
The promising immune checkpoint LAG-3: from tumor microenvironment to cancer immunotherapy.
Long Long, Xue Zhang, +4 authors, Honglei Chen.
Genes Cancer, 2019 Jan 04; 9(5-6). PMID: 30603054    Free PMC article.
Highly Cited. Review.
Tertiary lymphoid structures, drivers of the anti-tumor responses in human cancers.
Marie-Caroline Dieu-Nosjean, Nicolas A Giraldo, +3 authors, Catherine Sautès-Fridman.
Immunol Rev, 2016 Apr 19; 271(1). PMID: 27088920
Highly Cited. Review.
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.
Leena Gandhi, Delvys Rodríguez-Abreu, +27 authors, KEYNOTE-189 Investigators.
N Engl J Med, 2018 Apr 17; 378(22). PMID: 29658856
Highly Cited.
The Immunobiology of Kidney Cancer.
Charles G Drake, Mark N Stein.
J Clin Oncol, 2018 Oct 30;. PMID: 30372396
Review.
Wnt5a-induced M2 polarization of tumor-associated macrophages via IL-10 promotes colorectal cancer progression.
Qing Liu, Chaogang Yang, +10 authors, Bin Xiong.
Cell Commun Signal, 2020 Apr 02; 18(1). PMID: 32228612    Free PMC article.
Adenosinergic signaling as a target for natural killer cell immunotherapy.
Jiao Wang, Sandro Matosevic.
J Mol Med (Berl), 2018 Aug 03; 96(9). PMID: 30069747
Review.
Fc-dependent depletion of tumor-infiltrating regulatory T cells co-defines the efficacy of anti-CTLA-4 therapy against melanoma.
Tyler R Simpson, Fubin Li, +11 authors, Sergio A Quezada.
J Exp Med, 2013 Jul 31; 210(9). PMID: 23897981    Free PMC article.
Highly Cited.
Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†.
B Escudier, C Porta, +7 authors, ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org.
Ann Oncol, 2019 Feb 23; 30(5). PMID: 30788497
Highly Cited.
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.
Immunity, 2017 Feb 24; 46(2). PMID: 28228279    Free PMC article.
Highly Cited.
Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines.
T Pukrop, F Klemm, +5 authors, C Binder.
Proc Natl Acad Sci U S A, 2006 Mar 30; 103(14). PMID: 16569699    Free PMC article.
Highly Cited.
Expression and Mutation Patterns of PBRM1, BAP1 and SETD2 Mirror Specific Evolutionary Subtypes in Clear Cell Renal Cell Carcinoma.
Svenja Bihr, Riuko Ohashi, +9 authors, Peter Schraml.
Neoplasia, 2019 Jan 20; 21(2). PMID: 30660076    Free PMC article.
SETD2-dependent histone H3K36 trimethylation is required for homologous recombination repair and genome stability.
Sophia X Pfister, Sara Ahrabi, +8 authors, Timothy C Humphrey.
Cell Rep, 2014 Jun 17; 7(6). PMID: 24931610    Free PMC article.
Highly Cited.
Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma.
Nicolas A Giraldo, Etienne Becht, +13 authors, Catherine Sautès-Fridman.
Clin Cancer Res, 2017 Feb 19; 23(15). PMID: 28213366
Highly Cited.
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.
Highly Cited.
Metronomic cyclophosphamide regimen selectively depletes CD4+CD25+ regulatory T cells and restores T and NK effector functions in end stage cancer patients.
François Ghiringhelli, Cedric Menard, +7 authors, Bruno Chauffert.
Cancer Immunol Immunother, 2006 Sep 09; 56(5). PMID: 16960692
Highly Cited.
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.
Int J Cancer, 2021 Mar 13; 149(2). PMID: 33709428    Free PMC article.
Tumor-infiltrating regulatory dendritic cells inhibit CD8+ T cell function via L-arginine metabolism.
Lyse A Norian, Paulo C Rodriguez, +4 authors, Paul M Allen.
Cancer Res, 2009 Mar 19; 69(7). PMID: 19293186    Free PMC article.
Highly Cited.
Chemokines and chemokine receptors: an overview.
Raffaella Bonecchi, Emanuela Galliera, +3 authors, Alberto Mantovani.
Front Biosci (Landmark Ed), 2009 Mar 11; 14(2). PMID: 19273084
Review.
Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa.
Eric T Clambey, Eóin N McNamee, +8 authors, Holger K Eltzschig.
Proc Natl Acad Sci U S A, 2012 Sep 19; 109(41). PMID: 22988108    Free PMC article.
Highly Cited.
Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma.
Dan Huang, Yan Ding, +7 authors, Bin Tean Teh.
Cancer Res, 2010 Jan 28; 70(3). PMID: 20103651    Free PMC article.
Highly Cited.
Human Endogenous Retroviruses (HERVs): Shaping the Innate Immune Response in Cancers.
Vincent Alcazer, Paola Bonaventura, Stephane Depil.
Cancers (Basel), 2020 Mar 12; 12(3). PMID: 32155827    Free PMC article.
Review.
Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
Freddie Bray, Jacques Ferlay, +3 authors, Ahmedin Jemal.
CA Cancer J Clin, 2018 Sep 13; 68(6). PMID: 30207593
Highly Cited.
Cancer immunotherapy using checkpoint blockade.
Antoni Ribas, Jedd D Wolchok.
Science, 2018 Mar 24; 359(6382). PMID: 29567705    Free PMC article.
Highly Cited. Review.
Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.
David F McDermott, Mahrukh A Huseni, +29 authors, Thomas Powles.
Nat Med, 2018 Jun 06; 24(6). PMID: 29867230    Free PMC article.
Highly Cited.
Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.
Kaori Sakuishi, Lionel Apetoh, +3 authors, Ana C Anderson.
J Exp Med, 2010 Sep 08; 207(10). PMID: 20819927    Free PMC article.
Highly Cited.
Inferring tumour purity and stromal and immune cell admixture from expression data.
Kosuke Yoshihara, Maria Shahmoradgoli, +12 authors, Roel G W Verhaak.
Nat Commun, 2013 Oct 12; 4. PMID: 24113773    Free PMC article.
Highly Cited.
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.
Yasin Şenbabaoğlu, Ron S Gejman, +26 authors, A Ari Hakimi.
Genome Biol, 2016 Nov 20; 17(1). PMID: 27855702    Free PMC article.
Highly Cited.
Prognostic and Predictive Value of PBRM1 in Clear Cell Renal Cell Carcinoma.
Lucía Carril-Ajuria, María Santos, +2 authors, Guillermo de Velasco.
Cancers (Basel), 2019 Dec 22; 12(1). PMID: 31861590    Free PMC article.
Review.
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.
Cancer Immunol Immunother, 2019 Jan 18; 68(3). PMID: 30652208    Free PMC article.
Dangerous liaisons: STAT3 and NF-kappaB collaboration and crosstalk in cancer.
Sergei I Grivennikov, Michael Karin.
Cytokine Growth Factor Rev, 2009 Dec 19; 21(1). PMID: 20018552    Free PMC article.
Highly Cited. Review.
Resistance to PD1/PDL1 checkpoint inhibition.
Jake S O'Donnell, Georgina V Long, +2 authors, Mark J Smyth.
Cancer Treat Rev, 2016 Dec 13; 52. PMID: 27951441
Highly Cited. Review.
Tim-3 and its role in regulating anti-tumor immunity.
Madhumita Das, Chen Zhu, Vijay K Kuchroo.
Immunol Rev, 2017 Mar 05; 276(1). PMID: 28258697    Free PMC article.
Highly Cited. Review.
Pancreatic tropism of metastatic renal cell carcinoma.
Nirmish Singla, Zhiqun Xie, +18 authors, James Brugarolas.
JCI Insight, 2020 Apr 10; 5(7). PMID: 32271170    Free PMC article.
Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells.
Zaheed Husain, Yannu Huang, Pankaj Seth, Vikas P Sukhatme.
J Immunol, 2013 Jul 03; 191(3). PMID: 23817426
Highly Cited.
Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.
Jeffrey J Wallin, Johanna C Bendell, +19 authors, David F McDermott.
Nat Commun, 2016 Aug 31; 7. PMID: 27571927    Free PMC article.
Highly Cited.
Interleukin-6 induces drug resistance in renal cell carcinoma.
Kei Ishibashi, Tomoyuki Koguchi, +12 authors, Yoshiyuki Kojima.
Fukushima J Med Sci, 2018 Oct 30; 64(3). PMID: 30369518    Free PMC article.
Review.
Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.
Marco Gerlinger, Stuart Horswell, +22 authors, Charles Swanton.
Nat Genet, 2014 Feb 04; 46(3). PMID: 24487277    Free PMC article.
Highly Cited.
VEGF and FGF-2: Promising targets for the treatment of respiratory disorders.
Ankit P Laddha, Yogesh A Kulkarni.
Respir Med, 2019 Aug 20; 156. PMID: 31421589
Review.
Genetic basis of kidney cancer: role of genomics for the development of disease-based therapeutics.
W Marston Linehan.
Genome Res, 2012 Oct 06; 22(11). PMID: 23038766    Free PMC article.
Highly Cited.
NK Cell Metabolism and Tumor Microenvironment.
Iñigo Terrén, Ane Orrantia, +2 authors, Francisco Borrego.
Front Immunol, 2019 Oct 17; 10. PMID: 31616440    Free PMC article.
Review.
Prognostic Relevance of ZNF844 and Chr 19p13.2 KRAB-Zinc Finger Proteins in Clear Cell Renal Carcinoma.
Simone O Heyliger, Karam F A Soliman, Marilyn D Saulsbury, R Renee Reams.
Cancer Genomics Proteomics, 2022 Apr 18; 19(3). PMID: 35430565    Free PMC article.