Interferons induce CXCR3-cognate chemokine production by human metastatic melanoma - PubMed (original) (raw)
Interferons induce CXCR3-cognate chemokine production by human metastatic melanoma
Lynn T Dengel et al. J Immunother. 2010 Nov-Dec.
Abstract
Immune-mediated cancer regression requires tumor infiltration by antigen-specific effector T cells, but lymphocytes are commonly sparse in melanoma metastases. Activated T cells express CXCR3, whose cognate chemokines are CXCL9/MIG, CXCL10/IP-10, and CXCL11/I-TAC. Little is known about expression of these chemokines in lymph node (LN) metastases of melanoma. We evaluated whether metastatic melanoma induces these CXCR3-cognate chemokines in human LN-derived tissues. In addition, as these chemokines can be induced by interferon (IFN), we evaluated whether type I or II IFNs (IFN-α or IFN-γ, respectively) can modulate chemokine expression in an in vitro model of the human tumor microenvironment. Production of CXCL9-11 by melanoma-infiltrated nodes (MIN) was no different than tumor-free nodes; both produced less chemokine than activated LN (sentinel immunized nodes, SIN). These data suggest that melanoma infiltration into LN neither induces nor reduces CXCL9-11. Stimulation with IFN-α or IFN-γ increased production of CXCL10-11 from MIN, but not tumor-free node or SIN. IFN-γ also increased production of CXCL9 in MIN. In IFN-treated SIN, CD14+ cells were the primary source of CXCL9-11, whereas melanoma cells were the source of chemokine in MIN. Melanoma cells in MIN express IFN receptors. Consistent with these observations, multiple human melanoma lines expressed IFN receptors and produced CXCL9-11 in response to IFN treatment. Thus, melanoma infiltration of LN is insufficient to induce the production of CXCL9-11, but melanoma may be a significant source of IFN-induced chemokines. Collectively, these data suggest that IFN-α or IFN-γ may act in the tumor microenvironment to increase the chemotactic gradient for CXCR3+ T cells.
Conflict of interest statement
Disclosure of Potential Conflicts of Interest: The authors have no potential conflicts of interest.
Figures
Figure 1. SIN, but not TFN or MIN, produce CXCL9, CXCL10, and CXCL11
Viable cell suspensions from three tumor-free nodes (TFN), nine melanoma-infiltrated nodes (MIN) and three sentinel immunized lymph nodes (SIN) were cultured in 48 well plates at 5×105 mononuclear inflammatory cells per mL and incubated for 24 hours. The supernatants were then assessed for CXCL9 (A), CXCL10 (B), CXCL11 (C), and CCL21 (D) production by ELISA. Data are individual ELISA results from one of three independent assays with similar results. The horizontal line represents the mean of the population.
Figure 2. IFN treatment induced or increased the production of CXCL9, CXCL10, and CXCL11 in MIN, but not TFN or SIN
Viable cell suspensions from tumor-free nodes (TFN), melanoma-infiltrated (MIN), and sentinel immunized nodes (SIN) were plated in 48 well plates at 5×105 mononuclear inflammatory cells per mL and incubated with media alone, 1×105 IU of IFN-α, or 1×105 IU of IFN-γ for 24 hours. The supernatants were then assessed for CXCL9-11 production by ELISA. Data are means ± standard deviation of ELISA results from one of three independent assays. *, p < 0.05 vs. untreated; +, p < 0.01 vs. untreated.
Figure 3. Melanoma cells, but not CD14+ cells, produce CXCL9, CXCL10, and CXCL11 in response to IFN-γ treatment
A) Staining for S100 and CXCL9, CXCL10, or CXCL11 in melanoma-involved node (MIN) cell suspensions, gated on CD45-CD11c- populations. B) Staining for S100 and CXCL9, CXCL10, or CXCL11 in MIN suspensions gated on CD45+ cells. C) Staining for CD14 and CXCL9, CXCL10, or CXCL11 in tumor-free node (TFN) cell suspensions, gated to exclude dead cells and doublets. D) Staining for CD14 and CXCL9, CXCL10, or CXCL11 in sentinel immunized node (SIN) cell suspensions, gated to exclude dead cells and doublets. Data are representative from one of three similar experiments.
Figure 4. Melanoma cell lines produce CXCL9, CXCL10, and CXCL11 in response to IFN-α or IFN-γ treatment
Melanoma cell lines were cultured in 24 well plates at 1×106 cells per mL, either without or with 1×105 IU of IFN–α or IFN–γ for 24 hours. The supernatants were assayed in triplicate by ELISA for CXCL9 (A), CXCL10 (B), and CXCL11 (C). Data are means ± standard deviation of ELISA results from one of three independent assays.
Figure 5. Human melanoma cells express IFN-αR1 and IFN-γR1
A and B) Expression of IFN receptors on human melanoma cell lines DM93 (A) and DM331 (B). Data are representative of staining for 16 human melanoma cell lines evaluated (VMM5; VMM12; VMM15; VMM18; VMM19; VMM39; VMM150; MV3; SKMel2; DM6; DM13; DM14; DM122; and DM281, not shown) from one of three similar experiments. C) Representative data for IFN receptor expression on melanoma (CD45neg CD11cneg CD14neg S100+) cells in MIN, from one of six MIN samples tested.
Figure 6. Melanoma-derived factors fail to block IFN-induced production of CXCL9, CXCL10, and CXCL11 by whole blood cells
A-C) Chemokine production by whole blood samples following co-culture with melanoma supernatant and treatment with IFNs. Whole blood from a normal donor was incubated with escalating quantities of supernatant from a cultured melanoma cell line, either in media alone or with 1×105 IU of IFN–α or IFN–γ for 24h. The supernatants were assayed in triplicate by ELISA for CXCL9 (A), CXCL10 (B), and CXCL11 (C). Data are means ± standard deviation of pooled ELISA results from one of three independent assays using 6 normal donor patient samples.
Figure 7. IFN-γ-induced CXCL9 in peripheral blood-derived CD14+ cells is refractory to melanoma-derived factors
Normal donor PBL were incubated for 24h in media or with 1×105 IU of IFN–γ, and with or without supernatant (50% of culture) from the DM93 melanoma cell line. Cells were stained for CD14 and intracellular CXCL9. A) Staining for CD14 and CXCL9 in untreated PBL. B) Staining for CD14 and CXCL9 in IFN-γ-treated PBL. C) Staining for CD14 and CXCL9 in IFN-γ-treated PBL cultured with 50% melanoma supernatant. Data are representative from one of three similar experiments.
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