title: CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2.
abstract: BACKGROUND
  Adoptive therapy with tumour-infiltrating lymphocytes (TILs) induces durable complete responses (CR) in ∼20% of patients with metastatic melanoma. The recruitment of T cells through CXCR3/CCR5 chemokine ligands is critical for immune-mediated rejection. We postulated that polymorphisms and/or expression of CXCR3/CCR5 in TILs and the expression of their ligands in tumour influence the migration of TILs to tumours and tumour regression.
  
  
  METHODS
  Tumour-infiltrating lymphocytes from 142 metastatic melanoma patients enrolled in adoptive therapy trials were genotyped for CXCR3 rs2280964 and CCR5-Δ32 deletion, which encodes a protein not expressed on the cell surface. Expression of CXCR3/CCR5 in TILs and CXCR3/CCR5 and ligand genes in 113 available parental tumours was also assessed. Tumour-infiltrating lymphocyte data were validated by flow cytometry (N=50).
  
  
  RESULTS
  The full gene expression/polymorphism model, which includes CXCR3 and CCR5 expression data, CCR5-Δ32 polymorphism data and their interaction, was significantly associated with both CR and overall response (OR; P=0.0009, and P=0.007, respectively). More in detail, the predicted underexpression of both CXCR3 and CCR5 according to gene expression and polymorphism data (protein prediction model, PPM) was associated with response to therapy (odds ratio=6.16 and 2.32, for CR and OR, respectively). Flow cytometric analysis confirmed the PPM. Coordinate upregulation of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumour biopsies was associated with OR.
  
  
  CONCLUSIONS
  Coordinate overexpression of CXCL9, CXCL10, CXCL11, and CCL5 in pretreatment tumours was associated with responsiveness to treatment. Conversely, CCR5-Δ32 polymorphism and CXCR3/CCR5 underexpression influence downregulation of the corresponding receptors in TILs and were associated with likelihood and degree of response.
authors.affiliation: 1] Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, MD 20892, USA [2] Department of Oncology, Biology, Genetics (DOBIG), University of Genoa and National Cancer Research Institute, 16132 Genoa, Italy [3] Department of Internal Medicine (DiMI), University of Genoa, 16132 Genoa, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Bedognetti
authors.forename: T L
authors.initials: TL
authors.lastname: Spivey
authors.forename: Y
authors.initials: Y
authors.lastname: Zhao
authors.forename: L
authors.initials: L
authors.lastname: Uccellini
authors.forename: S
authors.initials: S
authors.lastname: Tomei
authors.forename: M E
authors.initials: ME
authors.lastname: Dudley
authors.forename: M L
authors.initials: ML
authors.lastname: Ascierto
authors.forename: V
authors.initials: V
authors.lastname: De Giorgi
authors.forename: Q
authors.initials: Q
authors.lastname: Liu
authors.forename: L G
authors.initials: LG
authors.lastname: Delogu
authors.forename: M
authors.initials: M
authors.lastname: Sommariva
authors.forename: M R
authors.initials: MR
authors.lastname: Sertoli
authors.forename: R
authors.initials: R
authors.lastname: Simon
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: S A
authors.initials: SA
authors.lastname: Rosenberg
authors.forename: F M
authors.initials: FM
authors.lastname: Marincola
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007376:Interleukin-2 / Q000627:therapeutic use*; D008024:Ligands; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D011110:Polymorphism, Genetic; D019713:Receptors, CCR5 / Q000235:genetics / Q000378:metabolism*; D054367:Receptors, CXCR3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D055815:Young Adult
chemical_list: C584933:CCR5 protein, human; C515187:CXCR3 protein, human; D007376:Interleukin-2; D008024:Ligands; D019713:Receptors, CCR5; D054367:Receptors, CXCR3