title: Orchestration and Prognostic Significance of Immune Checkpoints in the Microenvironment of Primary and Metastatic Renal Cell Cancer.
abstract: OBJECTIVE
  Clear cell renal cell carcinoma (ccRCC) has shown durable responses to checkpoint blockade therapies. However, important gaps persist in the understanding of its immune microenvironment. This study aims to investigate the expression and prognostic significance of immune checkpoints in primary and metastatic ccRCC, in relation with mature dendritic cells (DC) and T-cell densities.
  
  
  METHODS
  We investigated the infiltration and the localization of CD8(+) T cells and mature DC, and the expression of immune checkpoints (PD-1, LAG-3, PD-L1, and PD-L2) in relation with prognosis, in 135 primary ccRCC tumors and 51 ccRCC lung metastases. RNA expression data for 496 primary ccRCC samples were used as confirmatory cohort.
  
  
  RESULTS
  We identify two groups of tumors with extensive CD8(+) T-cell infiltrates. One group, characterized by high expression of immune checkpoints in the absence of fully functional mature DC, is associated with increased risk of disease progression. The second group, characterized by low expression of immune checkpoints and localization of mature DC in peritumoral immune aggregates (tertiary lymphoid structures), is associated with good prognosis.
  
  
  CONCLUSIONS
  The expression of the immune checkpoints and the localization of DC in the tumor microenvironment modulate the clinical impact of CD8(+) T cells in ccRCC.
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors: Nicolas A
authors: NA
authors: Giraldo
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors: Etienne
authors: E
authors: Becht
authors: Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. INSERM UMRS 1138, Cordeliers Research Center, Team 15 Integrative Cancer Immunology, Paris, France. Department of Immunology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Franck
authors: F
authors: Pagès
authors: CoStim Pharmaceuticals, Boston, Massachusetts.
authors: Georgios
authors: G
authors: Skliris
authors: Department of Pathology, Hôpital Necker-Enfants Malades, Paris, France.
authors: Virginie
authors: V
authors: Verkarre
authors: Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Yann
authors: Y
authors: Vano
authors: Department of Urology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Arnaud
authors: A
authors: Mejean
authors: Department of Urology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Nicolas
authors: N
authors: Saint-Aubert
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors: Laetitia
authors: L
authors: Lacroix
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors: Ivo
authors: I
authors: Natario
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. Department of Pathology, Hôpital Cochin, Paris, France.
authors: Audrey
authors: A
authors: Lupo
authors: Department of Thoracic Surgery, Hôpital Cochin, Paris, France.
authors: Marco
authors: M
authors: Alifano
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. Department of Pathology, Hôpital Cochin, Paris, France.
authors: Diane
authors: D
authors: Damotte
authors: Department of Pathology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Aurelie
authors: A
authors: Cazes
authors: Immutep, S.A., Orsay, France.
authors: Frederic
authors: F
authors: Triebel
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors: Gordon J
authors: GJ
authors: Freeman
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors: Marie-Caroline
authors: MC
authors: Dieu-Nosjean
authors: Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. Department of Medical Oncology, Hôpital Européen Georges Pompidou, Paris, France.
authors: Stephane
authors: S
authors: Oudard
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France.
authors: Wolf H
authors: WH
authors: Fridman
authors: INSERM, UMRS 1138, Cordeliers Research Center, Team 13 Cancer, Immune Control and Escape, Paris, France. Université Paris Descartes, Sorbonne Paris Cité, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. UPMC Univ Paris 06, Sorbonne Universités, UMRS 1138, Centre de Recherche des Cordeliers, Paris, France. catherine.fridman@crc.jussieu.fr.
authors: Catherine
authors: C
authors: Sautès-Fridman
mesh_terms: D015703:Antigens, CD / Q000378:metabolism; D060890:B7-H1 Antigen / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000401:mortality / Q000556:secondary; D018572:Disease-Free Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D007680:Kidney Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology; D015999:Multivariate Analysis; D011379:Prognosis; D061027:Programmed Cell Death 1 Ligand 2 Protein / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D016016:Proportional Hazards Models; D059016:Tumor Microenvironment; D000093322:Lymphocyte Activation Gene 3 Protein
chemical_list: D015703:Antigens, CD; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C105992:PDCD1 protein, human; C556977:PDCD1LG2 protein, human; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D000093322:Lymphocyte Activation Gene 3 Protein; C000720326:Lag3 protein, human