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 journalArticle

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
Pages (from-to)2412-2423
Number of pages12
JournalBritish Journal of Cancer
Volume109
Issue number9
DOIs
Publication statusPublished - Oct 29 2013

Keywords

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

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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  • Cite this

    Bedognetti, D., Spivey, T. L., Zhao, Y., Uccellini, L., Tomei, S., Dudley, M. E., Ascierto, M. L., De Giorgi, V., Liu, Q., Delogu, L. G., Sommariva, M., Sertoli, M. R., Simon, R., Wang, E., Rosenberg, S. A., & Marincola, F. M. (2013). CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2. British Journal of Cancer, 109(9), 2412-2423. https://doi.org/10.1038/bjc.2013.557