title: PD-1 blockade therapy in renal cell carcinoma: current studies and future promises.
abstract: RCC is considered an immunogenic tumor with a prominent dysfunctional immune cell infiltrate, unable to control tumor growth. Evasion of immune surveillance, a process defined immune-editing, leads to malignant progression. The striking improvement of knowledge in immunology has led to the identification of immune checkpoints (such as CTLA-4 and PD-1), whose blockage enhances the antitumor immunity. The interaction between PD-1, an inducible inhibitory receptor expressed on lymphocytes and DCs, and PD-L1 ligand, expressed by tumor cells, results in a down-regulation of the T-cell response. Therefore, the PD-1/PD-L1 axis inhibition by targeted-antibodies, increasing the T-cell proliferation and cytotoxicity, represents a promising mechanism to stimulate the anti-tumor activity of the immune system, improving the outcomes of cancer patients. Several PD-1 and PD-L1 inhibitors have been evaluated in different tumor types, showing promising results. The interesting correlation between lymphocytes PD-1 expression and RCC advanced stage, grade and prognosis, as well as the selective PD-L1 expression by RCC tumor cells and its potential association with worse clinical outcomes, have led to the development of new anti PD-1/PD-L1 agents, alone or in combination with anti-angiogenic drugs or other immunotherapeutic approaches, for the treatment of RCC. In this review we discuss the role of PD-1/PD-L1 in RCC, focusing on the biological rationale, current clinical studies and promising therapeutic perspectives to target the PD-1 pathway.
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Piazzale L.A. Scuro 10, 37124 Verona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Massari
authors.affiliation: Clinica di Oncologia Medica, AOU "Ospedali Riuniti", Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy. Electronic address: mattymo@alice.it.
authors.forename: M
authors.initials: M
authors.lastname: Santoni
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Piazzale L.A. Scuro 10, 37124 Verona, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Ciccarese
authors.affiliation: Department of Medical Oncology, University Campus Bio-Medico Roma, Oncologia Medica, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Santini
authors.affiliation: SSD Oncologia medica Tumori Testa e Collo, Fondazione IRCCS - Istituto Nazionale dei Tumori, Via Venezian, 1, 20133 Milano, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Alfieri
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Piazzale L.A. Scuro 10, 37124 Verona, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Martignoni
authors.affiliation: Department of Pathology and Diagnostic, Azienda Ospedaliera Universitaria Integrata, University of Verona, Piazzale L.A. Scuro 10, 37124 Verona, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Brunelli
authors.affiliation: Department of Specialistic Clinical and Odontostomatological Sciences, Polytechnic University of Marche, 60131 Ancona, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Piva
authors.affiliation: Clinica di Oncologia Medica, AOU "Ospedali Riuniti", Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Berardi
authors.affiliation: Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Montironi
authors.affiliation: Medical Oncology, IRCCS San Matteo University Hospital Foundation, piazzale C. Golgi 19, 27100 Pavia, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Porta
authors.affiliation: Clinica di Oncologia Medica, AOU "Ospedali Riuniti", Polytechnic University of the Marche Region, via Conca 71, 60126 Ancona, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Cascinu
authors.affiliation: Medical Oncology, Azienda Ospedaliera Universitaria Integrata, University of Verona, Piazzale L.A. Scuro 10, 37124 Verona, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Tortora
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D000970:Antineoplastic Agents / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002986:Clinical Trials as Topic; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D000074324:Ipilimumab; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D000077594:Nivolumab; D011379:Prognosis; D061026:Programmed Cell Death 1 Receptor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D000074324:Ipilimumab; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000077594:Nivolumab; C000594389:atezolizumab; C585832:pidilizumab; C582435:pembrolizumab; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: Immunotherapy; PD-1; PDL-1; Renal cell carcinoma