Purpose: CD4 + T cells play a central role in initiating and maintaining anticancer immune responses. However, regulatory CD4 + CD25 + T cells which express Foxp3 have also been shown to inhibit antitumor effector T cells. In view of these heterogeneous CD4 + T-cell populations, this study was designed to determine the prognostic value of various tumor-infiltrating CD4 + T-cell populations in head and neck squamous cell carcinoma. Experimental Design: Eighty-four newly diagnosed untreated patients with histologically proven primary head and neck squamous cell carcinoma were included in this study. Double or triple immunofluorescence staining was done to assess and quantify the activated CD4 + T cells are positively correlated with locoregional control may be through downregulation of harmful inflammatory reaction, which could favor tumor progression.

Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor A (TNFA), etc.]. A correlation between high intratumoral IL-15 concentrations and poor clinical outcome in lung and head and neck cancer patients has been recently reported. The purpose of this study was to investigate the role of the soluble A chain of IL-15 receptor (sIL-15RA), a natural regulator of IL-15, in head and neck cancer. Fifty-three newly diagnosed untreated head and neck cancer patients were included in this study. Quantification of sIL-15RA was performed with a newly developed RIA. Increased serum sIL-15RA concentrations were found in head and neck cancer patients and were closely correlated with poor clinical outcome both in terms of locoregional control and survival even on multivariate analysis. sIL-15RA was mainly produced by tumor cells via proteolytic cleavage of IL-15RA mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15RA concentrations. Surprisingly, sIL-15RA did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15-induced proinflammatory cytokines TNFA, that may promote tumor progression. This new tumor evasion mechanism based on amplification of the intratumoral inflammatory reaction is probably not restricted to head and neck cancer, as other tumors have been shown to release sIL-15RA. Overall, these results support for the first time an original protumor role of sIL-15RA in cancer.

SummaryIn a series of 84 head and neck patients, a statistically significant correlation was observed between high serum soluble interleukin (IL)-2 receptor alpha (sIL-2Ra) (P = 0·034) and metalloproteinase-9 (MMP-9) concentrations (P = 0·036) at diagnosis and a shorter survival of these patients. As MMP-9 has been shown to mediate cleavage of IL-2Ra (CD25) by preactivated T cells, we looked for a relationship between MMP-9 expression and soluble IL-2Ra serum concentrations in these cancer patients. We did not find any correlation between intratumoral expression of MMP-9 or serum MMP-9 concentrations and serum sIL-2Ra levels. These results led us to reassess the role of MMP-9 in the release of sIL-2Ra. Treatment of Kit225 leukaemic cells with recombinant MMP-9 slightly decreased membrane CD25 expression and was associated with an increased concentration of sIL-2Ra in the supernatants. However, using a selective inhibitor of MMP-9 we did not succeed in specifically inhibiting the release of sIL-2Ra by the Kit225 cell line or by phytohaemagglutinin (PHA)-activated peripheral blood mononuclear cells. In addition, in a preclinical mouse model, basal serum sIL-2Ra concentrations and sIL-2Ra production by activated cells were not altered in MMP-9-deficient mice compared to wild-type mice. Interestingly, a broad spectrum metalloproteinase inhibitor inhibited the release of sIL-2Ra by PHAactivated peripheral blood mononuclear cells, suggesting that in contrast with current views concerning the major role of MMP-9 in the cleavage of membrane IL-2Ra, other proteases are involved in the shedding of sIL-2Ra. MMP-9 and sIL-2Ra appear therefore as independent prognostic markers in head and neck cancers.

Supplementary Table S2 from Prognostic Value of Tumor-Infiltrating CD4⁺ T-Cell Subpopulations in Head and Neck Cancers

Supplementary Figure 3 from The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

Supplementary Figure Legends 1-5 from The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

Supplementary Figure Legends 1-5 from The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

Supplementary Methods from The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer