CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2

D. Bedognetti, T. L. Spivey, Y. Zhao, L. Uccellini, S. Tomei, M. E. Dudley, M. L. Ascierto, V. De Giorgi, Q. Liu, L. G. Delogu, M. Sommariva, M. R. Sertoli, R. Simon, E. Wang, S. A. Rosenberg, F. M. Marincola

Research output: Contribution to journalArticlepeer-review

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.Conclusion: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.

Original languageEnglish (US)
Pages (from-to)2412-2423
Number of pages12
JournalBritish journal of cancer
Volume109
Issue number9
DOIs
StatePublished - Oct 29 2013

Keywords

  • chemokines
  • immunotherapy
  • interlukin-2
  • melanoma
  • tumour microenvironment

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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