CXCR3/CCR5 pathways in metastatic melanoma patients treated with adoptive therapy and interleukin-2
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 a...
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Veröffentlicht in: | British journal of cancer 2013-10, Vol.109 (9), p.2412-2423 |
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Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 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. |
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ISSN: | 0007-0920 1532-1827 |
DOI: | 10.1038/bjc.2013.557 |