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

PDF file - 109K, CD4+CD8dim or CD4+NKG2D+ T cells can be found in other malignancies.

PDF file - 84K, The combination therapy induced a profound lymphopenia.

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

PDF file - 38K, Synergistic effects of TCR or IL-15 stimulation with NKG2D engagement for Th1 polarization in CD4+NKG2D+T cells.

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

PDF file - 94K, 2D Clustering of LogRatios (D21/D0) of gene expression post- (D21) and pre-therapy (D0) with sorafenib/temozolomide.

PDF file - 1795K, T-cell infiltration and MICA/B expression in metastatic melanoma.

Supplementary Figure 1 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 Tables 1-4 from The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Rα in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint–blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an “adjuvant” molecule capable of inducing or restoring IL-15Rα/IL-15 in tumors expressing MHC class I–related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells. Cancer Res; 74(1); 68–80. ©2013 AACR.

PDF file - 25K, Schedule of the sorafenib and temozolomide combination regimen.

Supplementary Figure 2 from The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

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Interleukin (IL)-15 is a proinflammatory cytokine, as it induces the production of inflammatory cytokines [IL-6, tumor necrosis factor α (TNFα), IL-17, 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 α chain of IL-15 receptor (sIL-15Rα), 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-15Rα was performed with a newly developed RIA. Increased serum sIL-15Rα 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-15Rα was mainly produced by tumor cells via proteolytic cleavage of IL-15Rα mediated by ADAM-17. A correlation was observed between ADAM-17 expression in tumor cells and serum sIL-15Rα concentrations. Surprisingly, sIL-15Rα did not act in vitro as an IL-15 antagonist but rather as an enhancer of IL-15–induced proinflammatory cytokines (IL-6, TNFα, and IL-17) 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-15Rα. Overall, these results support for the first time an original protumor role of sIL-15Rα in cancer. [Cancer Res 2008;68(10):3907–14]

Supplementary Figure 4 from The Soluble α Chain of Interleukin-15 Receptor: A Proinflammatory Molecule Associated with Tumor Progression in Head and Neck Cancer

Interleukin-15 and interleukin-2 are two hematopoietic cytokines belonging to γc family and both share the IL2/15Rβ chain and the common γ chain. The IL-15Rα and IL-2Rα chains confer specific binding and signalling for IL-15 and IL-2 respectively. IL-15 and IL-2 induce T-cell proliferation, effector T-cell differentiation and memory T-cell survival. Unlike IL-15, IL-2 plays a crucial role, in development and activation of regulatory T cells, which constitutively express specific IL-2Rα chain. In order to inhibit IL-2 and IL-15 dependent effector functions, we developed an original antagonist called BinhG which target the shared IL-2/15Rβγ receptor. To characterize BinhG's mechanism and therapeutic potential, we first studied its effect in vitro on IL-15 and IL-2-induced proliferation on cell lines and peripheral blood mononuclear cells. We found that BinhG was able to inhibit IL-15 and IL-2-dependent proliferation of effector NK and CD8 T cells expressing the IL-2/15Rβγ dimeric receptor, whereas it was unable to inhibit IL-2 induced-T-reg cells due to ILtheirs IL-2Rα expression. These results were confirmed in vivo, by inhibition of IL-2 or IL-15 induced activation in mice. Moreover, after PolyIC stimulation in vivo, BinhG was able to reduce IFNγ secretion by NK cells and activation marker CD69 surface expression by CD4 T and CD8 T lymphocytes, but has no effect on T-reg cells. In the light of these observations, BinhG was evaluated in order to induce tolerance. Thus, we set up a murine model of skin graft rejection, and we observed that BinhG prolonged the skin graft survival. The use of the BinhG antagonist appears to have much promise, as it is able to shift immune response towards the tolerance side of the balance. However, further studies are needed to maximize the therapeutic outcome, by improving BinhG in vivo half-life. Moreover, it would be of interest to evaluate BinhG's effect in autoimmune contexts. Citation Format: Meghnem Dihia, Sebastien Morisseau, Kilian Trillet, Marie Frutoso, Isabelle Barbieux, Agnes Quemener, Yannick Jacques, Erwan Mortier. A novel IL-2 and IL-15 antagonist shifting the immune balance towards tolerance: Potential therapeutic applications [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B033.

The prospect of effective immunotherapies for the treatment of patients with cancer is now becoming a clinical reality. Different major phenotypes of tumor microenvironment are emerging and could require distinct immunotherapeutic interventions for maximal therapeutic effect. In the T-cell infiltrated tumors context, monoclonal antibody blocking the PD-1/PD-L1 pathway, like nivolumab or lambrolizumab, have shown very promising clinical efficacy for patients with metastatic melanoma (MM), Non Small Cell Lung cancer and renal cell carcinoma (1, 2). Recently, the combination of nivolumab and ipilimumab (anti CTLA-4) has demonstrated a strong synergy in MM patients (3). Thus, blocking peripheral tolerance mechanisms such as CTLA-4 and PD1 molecules seems to be a very promising strategy to cure such cancers. Many combinations with other immunotherapeutic interventions seem encouraging to be evaluated in early clinical trials. Leveraging or consolidating the driving forces between the efficacy of such checkpoint inhibitors with novel activating or inhibiting immunomodulatory agents is crucial and has to be based on relevant pharmacological and preclinical models. RLI is a sushi-IL-15Rα/IL-15 fusion protein that mimics the IL-15 transpresentation (4). In this study, the immunomodulatory activities induced by RLI were evaluated in vivo in mice and ex-vivo on human samples. We showed that RLI induced a strong expansion and increased effector functions and differentiation of NK and CD8+ T cells without any induction/activation of regulatory CD4+ T cells (Treg). Comparison of equimolar doses of RLI, IL-15 and IL-2, led to the conclusion that RLI is much more effective than IL-15 for the induction of NK and CD8+ T cells and increased the ratio of NK to Treg cells. Beside, RLI appeared as a safe, specific and potent IL-15Rβ/γ receptor agonist. We then investigated potential synergy with anti-PD1 treatment in the CT26 preclinical mouse tumor model. Anti-PD1 and RLI concomitant treatment induced 31% of complete tumor regressions (CR) in the tumor model, while anti-PD1 as standalone treatment induced 6% of CR. The underlying mechanisms of this synergy will be presented during the AACR meeting. Altogether, this work provides evidence that RLI can enhance anti-tumor activity of anti-PD1 treatment. As RLI was shown to present a favorable safety profile in different animal species, these results are very encouraging and warrant its investigation in early clinical trials in the coming years. (1) Topalian SL et al. N Engl J Med. 2012 (2) Hamid O et al. N Engl J Med. 2013 (3) Wolchok JD et al. N Engl J Med. 2013 (4) Mortier E, et al. J Biol Chem. 2006 Citation Format: Mélanie Desbois, Coralie Beal, Clelia Coutzac, Magali Terme, Geraldine Teppaz, Sebastien Morisseau, David Bechard, Erwan Mortier, Nathalie Chaput. RLI, a sushi-IL-15Rα/IL-15 fusion protein, is a potent immunomodulatory agent on NK and CD8+ T cells and synergizes with anti-PD1 treatment in preclinical mouse tumor models. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2577. doi:10.1158/1538-7445.AM2014-2577