{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T17:07:49Z","timestamp":1782493669531,"version":"3.54.5"},"reference-count":121,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,10,27]],"date-time":"2020-10-27T00:00:00Z","timestamp":1603756800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS KAKENHI","award":["16K20159"],"award-info":[{"award-number":["16K20159"]}]},{"name":"JSPS KAKENHI","award":["26861290"],"award-info":[{"award-number":["26861290"]}]},{"name":"Nara Medical University Grant-in-Aid for the Collaborative Research Projects","award":["Fiscal Years. 2015\u20132016"],"award-info":[{"award-number":["Fiscal Years. 2015\u20132016"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Over the past decade, an \u201cimmunotherapy tsunami\u201d, more specifically that involving immune checkpoint inhibitors (ICIs), has overtaken the oncological field. The interaction and cross-talk among tumor cells and several immune cells in the tumor microenvironment are dynamic and complex processes. As immune contexture can vary widely across different types of primary tumors and tumor microenvironments, there is still a significant lack of clinically available definitive biomarkers to predict patient response to ICIs, especially in urogenital malignancies. An increasing body of evidence evaluating urological malignancies has proven that tumor-infiltrating lymphocytes (TILs) are a double-edged sword in cancer. There is an urgent need to shed light on the functional heterogeneity in the tumor-infiltrating immune system and to explore its prognostic impact following surgery and other treatments. Notably, we emphasized the difference in the immunological profile among urothelial carcinomas arising from different primary origins, the bladder, renal pelvis, and ureter. Significant differences in the density of FOXP3-positive TILs, CD204-positive tumor-infiltrating macrophages, PD-L1-positive cells, and colony-stimulating factors were observed. This review discusses two topics: (i) the prognostic impact of TILs and (ii) predictive biomarkers for ICIs, to shed light on lymphocyte migration in four solid tumors, the urothelial carcinoma, renal cell carcinoma, prostate cancer, and retroperitoneal sarcoma.<\/jats:p>","DOI":"10.3390\/cancers12113153","type":"journal-article","created":{"date-parts":[[2020,10,29]],"date-time":"2020-10-29T21:21:00Z","timestamp":1604006460000},"page":"3153","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Clinical Impact of Tumor-Infiltrating Lymphocytes and PD-L1-Positive Cells as Prognostic and Predictive Biomarkers in Urological Malignancies and Retroperitoneal Sarcoma"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9503-7356","authenticated-orcid":false,"given":"Makito","family":"Miyake","sequence":"first","affiliation":[{"name":"Department of Urology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9514-9964","authenticated-orcid":false,"given":"Shunta","family":"Hori","sequence":"additional","affiliation":[{"name":"Department of Urology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Owari","sequence":"additional","affiliation":[{"name":"Department of Urology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Oda","sequence":"additional","affiliation":[{"name":"Department of Urology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Tatsumi","sequence":"additional","affiliation":[{"name":"Department of Urology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Nakai","sequence":"additional","affiliation":[{"name":"Department of Urology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7207-4127","authenticated-orcid":false,"given":"Tomomi","family":"Fujii","sequence":"additional","affiliation":[{"name":"Department of Diagnostic Pathology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1507-2464","authenticated-orcid":false,"given":"Kiyohide","family":"Fujimoto","sequence":"additional","affiliation":[{"name":"Department of Urology, Nara Medical University, Nara 634-8522, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,10,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","article-title":"Oncology meets immunology: The cancer-immunity cycle","volume":"39","author":"Chen","year":"2013","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1038\/nature21349","article-title":"Elements of cancer immunity and the cancer\u2013immune set point","volume":"541","author":"Chen","year":"2017","journal-title":"Nature"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1007\/978-3-642-38007-5_23","article-title":"Inflammatory angiogenesis and the tumor microenvironment as targets for cancer therapy and prevention","volume":"159","author":"Bruno","year":"2014","journal-title":"Cancer Treat. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.rpor.2020.04.004","article-title":"Interplay between inflammation and cancer","volume":"25","author":"Piotrowski","year":"2020","journal-title":"Rep. Pract. Oncol. Radiother."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1111\/jcmm.14746","article-title":"Pan-cancer RNA-seq data stratifies tumours by some hallmarks of cancer","volume":"24","author":"Frost","year":"2020","journal-title":"J. Cell. Mol. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1016\/j.cell.2010.01.025","article-title":"Immunity, inflammation, and cancer","volume":"140","author":"Grivennikov","year":"2010","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.cell.2010.03.014","article-title":"Macrophage diversity enhances tumor progression and metastasis","volume":"141","author":"Qian","year":"2010","journal-title":"Cell"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Shembrey, C., Huntington, N.D., and Hollande, F. (2019). Impact of Tumor and Immunological Heterogeneity on the Anti-Cancer Immune Response. Cancers, 11.","DOI":"10.3390\/cancers11091217"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1016\/j.immuni.2013.10.003","article-title":"Spatiotemporal dynamics of intratumoral immune cells reveal the immune landscape in human cancer","volume":"39","author":"Bindea","year":"2013","journal-title":"Immunity"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s00011-013-0645-9","article-title":"Immune system: A double-edged sword in cancer","volume":"62","author":"Shantikumar","year":"2013","journal-title":"Inflamm. Res."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Bassani, B., Baci, D., Gallazzi, M., Poggi, A., Bruno, A., and Mortara, L. (2019). Natural Killer Cells as Key Players of Tumor Progression and Angiogenesis: Old and Novel Tools to Divert Their Pro-Tumor Activities into Potent Anti-Tumor Effects. Cancers, 11.","DOI":"10.3390\/cancers11040461"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"938","DOI":"10.1038\/nm.3909","article-title":"The prognostic landscape of genes and infiltrating immune cells across human cancers","volume":"21","author":"Gentles","year":"2015","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1158\/2326-6066.CIR-13-0028","article-title":"Immune Heterogeneity of Glioblastoma Subtypes: Extrapolation from the Cancer Genome Atlas","volume":"1","author":"Doucette","year":"2013","journal-title":"Cancer Immunol. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1158\/2159-8290.CD-17-0256","article-title":"TCR Repertoire Intratumor Heterogeneity in Localized Lung Adenocarcinomas: An Association with Predicted Neoantigen Heterogeneity and Postsurgical Recurrence","volume":"7","author":"Reuben","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"636","DOI":"10.1016\/j.neo.2016.08.002","article-title":"CXCL1-Mediated Interaction of Cancer Cells with Tumor-Associated Macrophages and Cancer-Associated Fibroblasts Promotes Tumor Progression in Human Bladder Cancer","volume":"18","author":"Miyake","year":"2016","journal-title":"Neoplasia"},{"key":"ref_17","first-page":"1139","article-title":"Turning cold tumors into hot tumors: Harnessing the potential of tumor immunity using nanoparticles","volume":"14","author":"Rodallec","year":"2018","journal-title":"Expert Opin. Drug Metab. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00262-017-2060-5","article-title":"Immunological classification of renal cell carcinoma patients based on phenotypic analysis of immune check-point molecules","volume":"67","author":"Kawashima","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s40425-018-0479-7","article-title":"High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors","volume":"6","author":"Vareki","year":"2018","journal-title":"J. Immunother. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"128","DOI":"10.3389\/fonc.2015.00128","article-title":"Immune infiltration and prostate Cancer","volume":"5","author":"Strasner","year":"2015","journal-title":"Front. Oncol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2685","DOI":"10.1158\/0008-5472.CAN-08-2654","article-title":"Coordination of Intratumoral Immune Reaction and Human Colorectal Cancer Recurrence","volume":"69","author":"Camus","year":"2009","journal-title":"Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.trecan.2017.11.005","article-title":"Inflammatory Reprogramming with IDO1 Inhibitors: Turning Immunologically Unresponsive \u2019Cold\u2019 Tumors \u2019Hot\u2019","volume":"4","author":"Prendergast","year":"2018","journal-title":"Trends Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.ccell.2015.10.012","article-title":"Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents","volume":"28","author":"Galluzzi","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_24","first-page":"251","article-title":"Emerging biomarkers for the diagnosis and monitoring of urothelial carcinoma","volume":"10","author":"Miyake","year":"2018","journal-title":"Res. Rep. Urol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"970","DOI":"10.1093\/annonc\/mdz127","article-title":"Randomized phase III KEYNOTE-045 trial of pembrolizumab versus paclitaxel, docetaxel, or vinflunine in recurrent advanced urothelial cancer: Results of >2 years of follow-up","volume":"30","author":"Fradet","year":"2019","journal-title":"Ann. Oncol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Miyake, M., Tatsumi, Y., Gotoh, D., Ohnishi, S., Owari, T., Iida, K., Ohnishi, K., Hori, S., Morizawa, Y., and Itami, Y. (2017). Regulatory T Cells and Tumor-Associated Macrophages in the Tumor Microenvironment in Non-Muscle Invasive Bladder Cancer Treated with Intravesical Bacille Calmette-Gu\u00e9rin: A Long-Term Follow-Up Study of a Japanese Cohort. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102186"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1007\/s00428-015-1808-6","article-title":"Correlation of tumor-infiltrating lymphocytes with bladder cancer recurrence in patients with solitary low-grade urothelial carcinoma","volume":"467","author":"Krpina","year":"2015","journal-title":"Virchows Arch."},{"key":"ref_28","first-page":"11510","article-title":"High CD4+ T cell density is associated with poor prognosis in patients with non-muscle-invasive bladder cancer","volume":"8","author":"Zhang","year":"2015","journal-title":"Int. J. Clin. Exp. Pathol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.1016\/j.prp.2018.05.010","article-title":"The prognostic values of tumor-infiltrating neutrophils, lymphocytes and neutrophil\/lymphocyte rates in bladder urothelial cancer","volume":"214","author":"Liu","year":"2018","journal-title":"Pathol. Res. Pract."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Yu, A., Mansure, J.J., Solanki, S., Siemens, D.R., Koti, M., Dias, A.B.T., Burnier, M.M., Brimo, F., and Kassouf, W. (2018). Presence of lymphocytic infiltrate cytotoxic T lymphocyte CD3+, CD8+, and immunoscore as prognostic marker in patients after radical cystectomy. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0205746"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.2147\/CMAR.S191105","article-title":"High CD3D\/CD4 ratio predicts better survival in muscle-invasive bladder cancer","volume":"11","author":"Shi","year":"2019","journal-title":"Cancer Manag. Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e1644108","DOI":"10.1080\/2162402X.2019.1644108","article-title":"Clinical impact of T cells, B cells and the PD-1\/PD-L1 pathway in muscle invasive bladder cancer: A comparative study of transurethral resection and cystectomy specimens","volume":"8","author":"Wahlin","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.clgc.2018.11.004","article-title":"Phenotypic Analysis of Tumor Tissue-Infiltrating Lymphocytes in Tumor Microenvironment of Bladder Cancer and Upper Urinary Tract Carcinoma","volume":"17","author":"Kawashima","year":"2019","journal-title":"Clin. Genitourin. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1007\/s12032-017-0941-2","article-title":"Prognostic significance of PD-L1 expression on tumor cells and tumor-infiltrating mononuclear cells in upper tract urothelial carcinoma","volume":"34","author":"Zhang","year":"2017","journal-title":"Med. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.1016\/j.juro.2017.06.086","article-title":"Prognostic Value of PD-1 and PD-L1 Expression in Patients with High Grade Upper Tract Urothelial Carcinoma","volume":"198","author":"Krabbe","year":"2017","journal-title":"J. Urol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"7725","DOI":"10.2147\/OTT.S222422","article-title":"The correlation of BER protein, IRF3 with CD8+ T cell and their prognostic significance in upper tract urothelial carcinoma","volume":"12","author":"Wang","year":"2019","journal-title":"Onco. Targets Ther."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7485","DOI":"10.1038\/s41598-018-25944-1","article-title":"Prognostic impact of tumor infiltrating lymphocytes on patients with metastatic urothelial carcinoma receiving platinum based chemotherapy","volume":"8","author":"Huang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"39916","DOI":"10.18632\/oncotarget.9537","article-title":"Tumor-infiltrating immune cell subpopulations influence the oncologic outcome after intravesical Bacillus Calmette-Gu\u00e9rin therapy in bladder cancer","volume":"7","author":"Pichler","year":"2016","journal-title":"Oncotarget"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1159\/000474780","article-title":"Changes on distribution of CD4+\/CD45RA- and CD8+\/CD11- cells in tumor-infiltrating lymphocytes of renal cell carcinoma associated with tumor progression","volume":"22","author":"Igarashi","year":"1992","journal-title":"Eur. Urol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1245","DOI":"10.1038\/s41467-019-09241-7","article-title":"Clonal architectures predict clinical outcome in clear cell renal cell carcinoma","volume":"10","author":"Huang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1564","DOI":"10.1111\/cas.13996","article-title":"Immune infiltration in renal cell carcinoma","volume":"110","author":"Zhang","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2174","DOI":"10.1158\/1078-0432.CCR-18-3206","article-title":"irRECIST for the Evaluation of Candidate Biomarkers of Response to Nivolumab in Metastatic Clear Cell Renal Cell Carcinoma: Analysis of a Phase II Prospective Clinical Trial","volume":"25","author":"Pignon","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1593\/tlo.13256","article-title":"Tumor-infiltrating PD1-Positive Lymphocytes and FoxP3-Positive Regulatory T Cells Predict Distant Metastatic Relapse and Survival of Clear Cell Renal Cell Carcinoma","volume":"6","author":"Kang","year":"2013","journal-title":"Transl. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1158\/1078-0432.CCR-08-1296","article-title":"Increased intratumoral FOXP3-positive regulatory immune cells during interleukin-2 treatment in metastatic renal cell carcinoma","volume":"15","author":"Jensen","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1111\/j.1464-410X.2008.08151.x","article-title":"The prognostic value of peritumoral regulatory T cells and its correlation with intratumoral cyclooxygenase-2 expression in clear cell renal cell carcinoma","volume":"103","author":"Li","year":"2009","journal-title":"BJU Int."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2075","DOI":"10.1158\/1078-0432.CCR-06-2139","article-title":"Tumor-infiltrating Foxp3\u2212CD4+CD25+ T cells predict poor survival in renal cell carcinoma","volume":"13","author":"Siddiqui","year":"2007","journal-title":"Clin. Cancer Res."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"6220","DOI":"10.1038\/s41598-020-63060-1","article-title":"Tumour grade significantly correlates with total dysfunction of tumour tissue-infiltrating lymphocytes in renal cell carcinoma","volume":"10","author":"Kawashima","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4416","DOI":"10.1158\/1078-0432.CCR-16-2848","article-title":"Tumor-Infiltrating and Peripheral Blood T-cell Immunophenotypes Predict Early Relapse in Localized Clear Cell Renal Cell Carcinoma","volume":"23","author":"Giraldo","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3419","DOI":"10.2147\/CMAR.S172039","article-title":"Checkpoint molecule PD-1-assisted CD8+ T lymphocyte count in tumor microenvironment predicts overall survival of patients with metastatic renal cell carcinoma treated with tyrosine kinase inhibitors","volume":"10","author":"Yao","year":"2018","journal-title":"Cancer Manag. Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1158\/1078-0432.CCR-10-2804","article-title":"Androgen deprivation boosts prostatic infiltration of cytotoxic and regulatory T lymphocytes and has no effect on disease-free survival in prostate cancer patients","volume":"17","author":"Sorrentino","year":"2011","journal-title":"Clin. Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1002\/pros.22862","article-title":"Infiltration of CD8+ lymphocytes is an independent prognostic factor of biochemical failure-free survival in prostate cancer","volume":"74","author":"Ness","year":"2014","journal-title":"Prostate"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1080\/15384047.2016.1235666","article-title":"Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse","volume":"17","author":"Nardone","year":"2016","journal-title":"Cancer Biol. Ther."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1658","DOI":"10.1002\/pros.23890","article-title":"Increased infiltration of CCR4-positive regulatory T cells in prostate cancer tissue is associated with a poor prognosis","volume":"79","author":"Watanabe","year":"2019","journal-title":"Prostate"},{"key":"ref_54","first-page":"190","article-title":"Integrative assessment of clinicopathological parameters and the expression of PD-L1, PD-L2 and PD-1 in tumor cells of retroperitoneal sarcoma","volume":"20","author":"Makito","year":"2020","journal-title":"Oncol. Lett."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1097\/PAS.0b013e31824f2594","article-title":"Lymphocyte composition and distribution in inflammatory, well-differentiated retroperitoneal liposarcoma: Clues to a potential adaptive immune response and therapeutic implications","volume":"36","author":"Tseng","year":"2012","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"547460","DOI":"10.1155\/2015\/547460","article-title":"Analysis of the intratumoral adaptive immune response in well differentiated and dedifferentiated retroperitoneal liposarcoma","volume":"2015","author":"Tseng","year":"2015","journal-title":"Sarcoma"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3038","DOI":"10.1111\/cas.14161","article-title":"Comprehensive immune characterization and T-cell receptor repertoire heterogeneity of retroperitoneal liposarcoma","volume":"110","author":"Yan","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Gevaert, T., Cimadamore, A., Montironi, R., and Eckstein, M. (2020). PD-L1 Testing for Urothelial Carcinoma: Interchangeability, Reliability and Future Perspectives. Curr. Drug Targets, 9.","DOI":"10.2174\/1389450121666200510015216"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/S1470-2045(17)30900-2","article-title":"Avelumab in metastatic urothelial carcinoma after platinum failure (javelin Solid Tumor): Pooled results from two expansion cohorts of an open-label, phase 1 trial","volume":"19","author":"Patel","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.1200\/JCO.19.00538","article-title":"Nivolumab Alone and with Ipilimumab in Previously Treated Metastatic Urothelial Carcinoma: CheckMate 032 Nivolumab 1 mg\/kg Plus Ipilimumab 3 mg\/kg Expansion Cohort Results","volume":"37","author":"Sharma","year":"2019","journal-title":"J. Clin. Oncol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"e172411","DOI":"10.1001\/jamaoncol.2017.2411","article-title":"Efficacy and safety of durvalumab in locally advanced or metastatic urothelial carcinoma: Updated results from a phase 1\/2 open-label study","volume":"3","author":"Powles","year":"2017","journal-title":"JAMA Oncol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/S1470-2045(17)30065-7","article-title":"Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial","volume":"18","author":"Sharma","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/S0140-6736(17)33297-X","article-title":"Atezolizumab versus chemotherapy in patients with platinum-treated locally advanced or metastatic urothelial carcinoma (IMvigor211): A multicentre, open-label, phase 3 randomised controlled trial","volume":"391","author":"Powles","year":"2018","journal-title":"Lancet"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1200\/JCO.19.02394","article-title":"Phase Ib\/II Clinical Trial of Pembrolizumab With Bevacizumab for Metastatic Renal Cell Carcinoma: BTCRC-GU14-003","volume":"38","author":"Dudek","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1154","DOI":"10.1200\/JCO.19.01598","article-title":"Phase IB\/II Trial of Lenvatinib Plus Pembrolizumab in Patients With Advanced Renal Cell Carcinoma, Endometrial Cancer, and Other Selected Advanced Solid Tumors","volume":"38","author":"Taylor","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1056\/NEJMoa1816714","article-title":"Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma","volume":"380","author":"Rini","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1056\/NEJMoa1816047","article-title":"Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma","volume":"380","author":"Motzer","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1370","DOI":"10.1016\/S1470-2045(19)30413-9","article-title":"Nivolumab plus ipilimumab versus sunitinib in first-line treatment for advanced renal cell carcinoma: Extended follow-up of efficacy and safety results from a randomised, controlled, phase 3 trial","volume":"20","author":"Motzer","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2404","DOI":"10.1016\/S0140-6736(19)30723-8","article-title":"Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): A multicentre, open-label, phase 3, randomised controlled trial","volume":"393","author":"Rini","year":"2019","journal-title":"Lancet"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1056\/NEJMoa041905","article-title":"Coronary-artery revascularization before elective major vascular surgery","volume":"351","author":"McFalls","year":"2004","journal-title":"N. Engl. J. Med."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1016\/S0140-6736(10)61389-X","article-title":"Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: A randomised open-label trial","volume":"376","author":"Oudard","year":"2010","journal-title":"Lancet"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1016\/S1470-2045(17)30624-1","article-title":"Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): A multicentre, two-cohort, single-arm, open-label, phase 2 trial","volume":"18","author":"Tawbi","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/S1470-2045(18)30006-8","article-title":"Nivolumab with or without ipilimumab treatment for metastatic sarcoma (Alliance A091401): Two open-label, non-comparative, randomised, phase 2 trials","volume":"19","author":"Mahoney","year":"2018","journal-title":"Lancet Oncol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1001\/jamaoncol.2019.6152","article-title":"Objective Response Rate Among Patients with Locally Advanced or Metastatic Sarcoma Treated With Talimogene Laherparepvec in Combination with Pembrolizumab: A Phase 2 Clinical Trial","volume":"6","author":"Kelly","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S1470-2045(19)30153-6","article-title":"Axitinib plus pembrolizumab in patients with advanced sarcomas including alveolar soft-part sarcoma: A single-centre, single-arm, phase 2 trial","volume":"20","author":"Wilky","year":"2019","journal-title":"Lancet Oncol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1016\/j.juro.2012.05.079","article-title":"Urothelial carcinoma of the bladder and the upper tract: Disparate twins","volume":"189","author":"Green","year":"2013","journal-title":"J. Urol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1007\/s00345-012-0946-6","article-title":"Distinct patterns and behaviour of urothelial carcinoma with respect to anatomical location: How molecular biomarkers can augment clinico-pathological predictors in upper urinary tract tumours","volume":"31","author":"Yates","year":"2013","journal-title":"World J. Urol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"764","DOI":"10.1111\/bju.14111","article-title":"Nishinihon Uro-Oncology Collaborative Group. Outcomes of subsequent non-muscle-invasive bladder cancer treated with intravesical Bacillus Calmette-Gu\u00e9rin after radical nephroureterectomy for upper urinary tract urothelial carcinoma","volume":"121","author":"Miyake","year":"2018","journal-title":"BJU Int."},{"key":"ref_80","first-page":"103","article-title":"Colony-stimulating factors detected in tumor cells and voided urine are potential prognostic markers for patients with muscle-invasive bladder cancer undergoing radical cystectomy","volume":"10","author":"Morizawa","year":"2018","journal-title":"Res. Rep. Urol."},{"key":"ref_81","first-page":"2237","article-title":"Evaluation of pro- and anti-tumor effects induced by three colony-stimulating factors, G-CSF, GM-CSF and M-CSF, in bladder cancer cells: Is G-CSF a friend of bladder cancer cells?","volume":"54","author":"Hori","year":"2019","journal-title":"Int. J. Oncol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1111\/cas.14158","article-title":"Supplementary granulocyte macrophage colony-stimulating factor to chemotherapy and programmed death-ligand 1 blockade decreases local recurrence after surgery in bladder cancer","volume":"110","author":"Hori","year":"2019","journal-title":"Cancer Sci."},{"key":"ref_83","first-page":"8459193","article-title":"Tumor-Associated CD204-Positive Macrophage Is a Prognostic Marker in Clinical Stage I Lung Adenocarcinoma","volume":"2018","author":"Sun","year":"2018","journal-title":"Biomed. Res. Int."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1056\/NEJMoa065044","article-title":"Sunitinib versus interferon alfa in metastatic renal-cell carcinoma","volume":"356","author":"Motzer","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1016\/S0140-6736(11)61613-9","article-title":"Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial","volume":"378","author":"Rini","year":"2011","journal-title":"Lancet"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1007\/s00345-004-0466-0","article-title":"Novel approaches in the therapy of metastatic renal cell carcinoma","volume":"23","author":"Lam","year":"2005","journal-title":"World J. Urol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1016\/j.mcna.2017.03.009","article-title":"Prevention of Prostate Cancer Morbidity and Mortality: Primary Prevention and Early Detection","volume":"101","author":"Barry","year":"2017","journal-title":"Med. Clin. N. Am."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1016\/j.eururo.2016.10.008","article-title":"Global Burden of Urologic Cancers, 1990\u20132013","volume":"71","author":"Dy","year":"2017","journal-title":"Eur. Urol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1014618","article-title":"Abiraterone and increased survival in metastatic prostate cancer","volume":"364","author":"Logothetis","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1056\/NEJMoa1405095","article-title":"Enzalutamide in metastatic prostate cancer before chemotherapy","volume":"371","author":"Beer","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1056\/NEJMoa1001294","article-title":"Sipuleucel-T immunotherapy for castration-resistant prostate cancer","volume":"363","author":"Kantoff","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1056\/NEJMoa1213755","article-title":"Alpha emitter radium-223 and survival in metastatic prostate cancer","volume":"369","author":"Parker","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1200\/JCO.19.01638","article-title":"Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study","volume":"38","author":"Antonarakis","year":"2020","journal-title":"J. Clin. Oncol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"e000642","DOI":"10.1136\/jitc-2020-000642","article-title":"A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone","volume":"8","author":"Graff","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1807","DOI":"10.1093\/annonc\/mdy232","article-title":"Pembrolizumab for advanced prostate adenocarcinoma: Findings of the KEYNOTE-028 study","volume":"29","author":"Hansen","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"700","DOI":"10.1016\/S1470-2045(14)70189-5","article-title":"Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial","volume":"15","author":"Kwon","year":"2014","journal-title":"Lancet Oncol."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/pros.20661","article-title":"Dominance of CD4+ lymphocytic infiltrates with disturbed effector cell characteristics in the tumor microenvironment of prostate carcinoma","volume":"68","author":"Ebelt","year":"2008","journal-title":"Prostate"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"e1672494","DOI":"10.1080\/2162402X.2019.1672494","article-title":"Tumor-infiltrating lymphocytes from human prostate tumors reveal anti-tumor reactivity and potential for adoptive cell therapy","volume":"8","author":"Yunger","year":"2019","journal-title":"Oncoimmunology"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1038\/pcan.2015.39","article-title":"Paucity of PD-L1 expression in prostate cancer: Innate and adaptive immune resistance","volume":"18","author":"Martin","year":"2015","journal-title":"Prostate Cancer Prostatic Dis."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"14565","DOI":"10.1073\/pnas.251140998","article-title":"T cell infiltration of the prostate induced by androgen withdrawal in patients with prostate cancer","volume":"98","author":"Mercader","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1016\/j.ajpath.2018.02.014","article-title":"Comprehensive Evaluation of Programmed Death-Ligand 1 Expression in Primary and Metastatic Prostate Cancer","volume":"188","author":"Haffner","year":"2018","journal-title":"Am. J. Pathol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/2045-3329-2-14","article-title":"The epidemiology of sarcoma","volume":"2","author":"Burningham","year":"2012","journal-title":"Clin. Sarcoma Res."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1016\/j.ejso.2016.10.032","article-title":"Primary retroperitoneal soft tissue sarcoma: Imaging appearances, pitfalls and diagnostic algorithm","volume":"43","author":"Messiou","year":"2017","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1002","DOI":"10.1097\/SLA.0000000000001447","article-title":"Variability in patterns of recurrence after resection of primary retroperitoneal sarcoma (RPS): A report on 1007 patients from the multiinstitutional collaborative RPS Working Group","volume":"263","author":"Gronchi","year":"2016","journal-title":"Ann. Surg."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2637","DOI":"10.1002\/cncr.32795","article-title":"Doxorubicin plus dacarbazine, doxorubicin plus ifosfamide, or doxorubicin alone as a first-line treatment for advanced leiomyosarcoma: A propensity score matching analysis from the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group","volume":"126","author":"Touati","year":"2020","journal-title":"Cancer"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"9757219","DOI":"10.1155\/2016\/9757219","article-title":"Current immunotherapies for sarcoma: Clinical trials and rationale","volume":"2016","author":"Mitsis","year":"2016","journal-title":"Sarcoma"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"e558","DOI":"10.1200\/EDBK_161901","article-title":"Manipulating the immune system with checkpoint inhibitors for patients with metastatic sarcoma","volume":"36","author":"Angelo","year":"2016","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/PAP.0000000000000161","article-title":"Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non-Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors","volume":"24","author":"Hendry","year":"2017","journal-title":"Adv. Anat. Pathol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"1547","DOI":"10.1016\/S0140-6736(20)30230-0","article-title":"Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): A multicentre, randomised, placebo-controlled phase 3 trial","volume":"395","author":"Galsky","year":"2020","journal-title":"Lancet"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"3967","DOI":"10.1073\/pnas.0611618104","article-title":"CD8 tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma","volume":"104","author":"Sharma","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_112","first-page":"420","article-title":"The relationships among tumor-infiltrating lymphocytes, histopathologic findings, and long-term clinical follow-up in renal cell carcinoma","volume":"5","author":"Kolbeck","year":"1992","journal-title":"Mod. Pathol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1906","DOI":"10.1038\/sj.bjc.6601400","article-title":"The relationship between T-lymphocyte infiltration, stage, tumour grade and survival in patients undergoing curative surgery for renal cell cancer","volume":"89","author":"Bromwich","year":"2003","journal-title":"Br. J. Cancer."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"4079","DOI":"10.1158\/1078-0432.CCR-12-3847","article-title":"Characteristics and Clinical Impacts of the Immune Environments in Colorectal and Renal Cell Carcinoma Lung Metastases: Influence of Tumor Origin","volume":"19","author":"Remark","year":"2013","journal-title":"Clin. Cancer Res."},{"key":"ref_115","first-page":"5132","article-title":"Proliferative Activity of Intratumoral CD8+ T-Lymphocytes As a Prognostic Factor in Human Renal Cell Carcinoma","volume":"61","author":"Nakano","year":"2001","journal-title":"Cancer Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1038\/bjc.2011.368","article-title":"Prognostic significance of CD45RO+ memory T cells in renal cell carcinoma","volume":"105","author":"Hotta","year":"2011","journal-title":"Br. J. Cancer."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0090-4295(99)00152-1","article-title":"High-grade inflammation in prostate cancer as a prognostic factor for biochemical recurrence after radical prostatectomy","volume":"54","author":"Irani","year":"1999","journal-title":"Urology"},{"key":"ref_118","first-page":"4435","article-title":"Tumour-infiltrating Lymphocytes: A Prognostic Factor of PSA-free Survival in Patients with Local Prostate Carcinoma Treated by Radical Prostatectomy","volume":"25","author":"Karja","year":"2005","journal-title":"Anticancer Res."},{"key":"ref_119","doi-asserted-by":"crossref","unstructured":"Zeigler-Johnson, C., Morales, K.H., Lal, P., and Feldman, M. (2016). The Relationship between Obesity, Prostate Tumor Infiltrating Lymphocytes and Macrophages, and Biochemical Failure. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0159109"},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/j.1365-2559.2008.03058.x","article-title":"The prognostic impact of M-CSF, CSF-1 receptor, CD68 and CD3 in prostatic carcinoma","volume":"53","author":"Richardsen","year":"2008","journal-title":"Histopathology"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/sj.bjc.6601943","article-title":"The relationship between T-lymphocyte subset infiltration and survival in patients with prostate cancer","volume":"91","author":"McArdle","year":"2004","journal-title":"Br. J. Cancer"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3153\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:29:20Z","timestamp":1760178560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3153"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,10,27]]},"references-count":121,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cancers12113153"],"URL":"https:\/\/doi.org\/10.3390\/cancers12113153","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,10,27]]}}}