Regulation of CD4+NKG2D+ Th1 cells in patients with metastatic melanoma treated with sorafenib : role of IL-15Rα and NKG2D triggering

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 MHCclass I-related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells.peer-reviewe

IL-15 trans-presentation promotes human NK cell development and differentiation in vivo

The in vivo requirements for human natural killer (NK) cell development and differentiation into cytotoxic effectors expressing inhibitory receptors for self–major histocompatability complex class I (MHC-I; killer Ig-like receptors [KIRs]) remain undefined. Here, we dissect the role of interleukin (IL)-15 in human NK cell development using Rag2−/−γc−/− mice transplanted with human hematopoietic stem cells. Human NK cell reconstitution was intrinsically low in this model because of the poor reactivity to mouse IL-15. Although exogenous human IL-15 (hIL-15) alone made little improvement, IL-15 coupled to IL-15 receptor α (IL-15Rα) significantly augmented human NK cells. IL-15–IL-15Rα complexes induced extensive NK cell proliferation and differentiation, resulting in accumulation of CD16+KIR+ NK cells, which was not uniquely dependent on enhanced survival or preferential responsiveness of this subset to IL-15. Human NK cell differentiation in vivo required hIL-15 and progressed in a linear fashion from CD56hiCD16−KIR− to CD56loCD16+KIR−, and finally to CD56loCD16+KIR+. These data provide the first evidence that IL-15 trans-presentation regulates human NK cell homeostasis. Use of hIL-15 receptor agonists generates a robust humanized immune system model to study human NK cells in vivo. IL-15 receptor agonists may provide therapeutic tools to improve NK cell reconstitution after bone marrow transplants, enhance graft versus leukemia effects, and increase the pool of IL-15–responsive cells during immunotherapy strategies

RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients

Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). ROR gamma t, the key Thelperl7 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and gamma delta-T cells, but their contribution to SpA is still unclear. Here we describe the presence of particular ROR gamma t(+)T-be(lo)PLZF(-) iNKT and gamma delta-hi T cell subsets in healthy peripheral blood. ROR gamma t(+) iNKT and gamma delta-hi T cells show IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and gamma delta-T cells showed unique and Th17-skewed phenotype and gene expression profiles. Strikingly, ROR gamma t inhibition blocked gamma delta 17 and iNKT17 cell function while selectively sparing IL-22(+) subsets. Overall, our findings highlight a unique diversity of human ROR gamma t(+) T cells and underscore the potential of ROR gamma t antagonism to modulate aberrant type 17 responses

Syndecan-1 regulates the biological activities of interleukin-34

IL-34 is a challenging cytokine sharing functional similarities with M-CSF through M-CSFR activation. It also plays a singular role that has recently been explained in the brain, through a binding to the receptor protein tyrosine phosphatase RPTPβ/ζ. The aim of this paper was to look for alternative binding of IL-34 on other cell types. Myeloid cells (HL-60, U-937, THP-1) were used as cells intrinsically expressing M-CSFR, and M-CSFR was expressed in TF-1 and HEK293 cells. IL-34 binding was studied by Scatchard and binding inhibition assays, using 125I-radiolabelled cytokines, and surface plasmon resonance. M-CSFR activation was analysed by Western blot after glycosaminoglycans abrasion, syndecan-1 overexpression or repression and addition of a blocking anti-syndecan antibody. M-CSF and IL-34 induced different patterns of M-CSFR phosphorylations, suggesting the existence of alternative binding for IL-34. Binding experiments and chondroitinase treatment confirmed low affinity binding to chondroitin sulphate chains on cells lacking both M-CSFR and RPTPβ/ζ. Amongst the proteoglycans with chondroitin sulphate chains, syndecan-1 was able to modulate the IL-34-induced M-CSFR signalling pathways. Interestingly, IL-34 induced the migration of syndecan-1 expressing cells. Indeed, IL-34 significantly increased the migration of THP-1 and M2a macrophages that was inhibited by addition of a blocking anti-syndecan-1 antibody. This paper provides evidence of alternative binding of IL-34 to chondroitin sulphates and syndecan-1 at the cell surface that modulates M-CSFR activation. In addition, IL-34-induced myeloid cell migration is a syndecan-1 dependent mechanism

Étude des Réactions de Cycloaddition Dipolaire-1,3 d'Ylures d'Azométhine formés in situ à partir des Acides Aminés et de leurs dérivés

1,3-Dipolar Cycloaddition Reaction Study of Azomethine Ylides derived from alpha Amino AcidsLe mémoire concerne l'étude des réactions de cycloaddition dipolaire-1,3 inter et intramoléculaire d'ylures d'azométhine formés in situ à partir des acides alpha aminés et de leur dérivés avec les composés carbonylés

Etude des reactions de cycloaddition dipolaire-1,3 d'ylures d'azomethine formes in situ a partir des acides amines et de leurs derives

SIGLECNRS TD Bordereau / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Mise en évidence d'une forme soluble de la chaîne alpha du récepteur de l'interleukine-15 humaine (caractérisation structurale et fonctionnelle)

L'Interleukine-15 (IL-15) est une cytokine qui présente des activités semblables à celles de l'IL-2 in vitro du fait de l'utilisation commune des chaînes réceptrices IL-2Rb et gc, la spécificité d'action étant conférée par une chaîne réceptrice alpha. L'IL-2Ralpha existe sous forme soluble après clivage protéolytique de la forme membranaire. Dans cette étude, nous avons mis en évidence in vitro puis in vivo une forme soluble de la chaîne IL-15Ralpha issue du clivage de l'IL-15Ralpha membranaire et possédant une forte activité antagoniste de l'action de l'IL-15. Le domaine N-terminal de l'IL-15Ralpha (sIL-15Ralpha-sushi) en combinaison avec l'IL-15, s'avère être, quant à lui, agoniste pour les cellules n'exprimant que les chaînes IL-2Rb et gc, effet renforcé par la liaison IL-15/sIL-15Ralpha grâce à un linker. Ce travail montre que le sIL-15Ralpha est une composante importante dans la régulation des activités de l'IL-15 et pourrait conduire à différentes applications thérapeutiques.Interleukin-15 (IL-15) mimics most of the in vitro biological activity elicited by IL-2. This redundancy is explained by the common usage of the two receptors IL-2Rb and gc. Cytokine specificity is conferred by private alpha chains. IL-2Ralpha exists as a soluble form shed from the membrane-bound form. In this study, we identify in vitro and then in vivo a soluble form of the IL-15Ralpha chain, stemmed from membrane-bound IL-15Ralpha and which is a strong antagonist of IL-15 activity. The N-terminal domain of IL-15Ralpha (sIL-15Ralpha-sushi) , in combination with IL-15 exerts an agonistic effect on IL-2Rb/gc expressing cells, an effect strenghtened by covalently linking IL-15 to sIL-15Ralpha. This work shows that sIL-15Ralpha plays important roles in regulation of IL-15 activity and could lead to therapeutic applications.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF