SIRPα blockade reinvigorates myeloid cells in the tumor microenvironment and reverses T-cell exclusion

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SIRP α/CD 47 axis controls the maintenance of transplant tolerance sustained by myeloid‐derived suppressor cells

International audienceMyeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature hematopoietic precursors known to suppress immune responses. Interaction of SIRP alpha (SIRPα), expressed by myeloid cells, with the ubiquitous receptor CD47 is an important immune checkpoint of the innate response regulating macrophages and dendritic cells functions. We previously described that MDSC expressing SIRPα accumulated after transplantation and maintained kidney allograft tolerance. However, the role of the SIRPα/CD47 axis on MDSC function remained unknown. Here, we found that blocking SIRPα or CD47 with monoclonal antibodies (mAbs) induced differentiation of MDSC into myeloid cells overexpressing MHC class II, CD86 costimulatory molecule and increased secretion of macrophage-recruiting chemokines (eg, MCP-1). Using a model of long-term kidney allograft tolerance sustained by MDSC, we observed that administration of blocking anti-SIRPα or CD47 mAbs induced graft dysfunction and rejection. Loss of tolerance came along with significant decrease of MDSC and increase in MCP-1 concentration in the periphery. Graft histological and transcriptomic analyses revealed an inflammatory (M1) macrophagic signature at rejection associated with overexpression of MCP-1 mRNA and protein in the graft. These findings indicate that the SIRPα-CD47 axis regulates the immature phenotype and chemokine secretion of MDSC and contributes to the induction and the active maintenance of peripheral acquired immune tolerance

Interleukin‐7/Interferon axis drives T‐cell and salivary gland epithelial cell interactions in Sjögren’s syndrome

International audienceObjectivePrimary Sjögren’s syndrome (pSS) is characterized by a lymphocytic infiltration of salivary glands and the presence of an interferon (IFN) signature. Salivary gland epithelial cells (SGECs) play an active role in pSS pathophysiology. The aim of this work was to study the interactions between SGECs and T cells in pSS and the role of the IL‐7/IFN axis.MethodsPrimary cultured SGECs from pSS and controls were stimulated with poly(I:C), IFNα or IFNγ. T cells were sorted from blood and stimulated with IL‐7. CD25 expression was assessed by flow cytometry. Salivary gland explants were cultured for 4 days with anti‐IL‐7R antagonist antibody (OSE‐127) and transcriptomic analysis was performed by using nanostring.ResultsIL‐7 serum level was increased in pSS patients versus controls and was associated with B‐cell biomarkers. IL7R expression was decreased in T cells from pSS patients versus controls. SGECs stimulated with poly(I:C), IFNα, or IFNγ secreted IL‐7. IL‐7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of salivary gland explants showed a correlation between IL7 and IFN expression. Lastly, explants cultured with anti‐IL‐7R antibody showed decreased IFN‐stimulated gene expression.ConclusionThese results suggest an IL‐7‐IFNγ amplification loop involving SGECs and T cells in pSS. IL‐7 was secreted by SGECs stimulated with type 1 or type 2 IFN and, in turn, activate T cells that secrete type 2 IFN. An anti‐IL‐7R antibody decreased the IFN signature in T cells during pSS and could be of therapeutic interest

Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

International audienceBelatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 (n=5), a selective pegylated Fab9 antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept (n=5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid-resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell-specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro, FR104 controlled the proliferative response of human preex-isting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation

Interleukin‐7/Interferon axis drives T‐cell and salivary gland epithelial cell interactions in Sjögren’s syndrome

International audienceObjectivePrimary Sjögren’s syndrome (pSS) is characterized by a lymphocytic infiltration of salivary glands and the presence of an interferon (IFN) signature. Salivary gland epithelial cells (SGECs) play an active role in pSS pathophysiology. The aim of this work was to study the interactions between SGECs and T cells in pSS and the role of the IL‐7/IFN axis.MethodsPrimary cultured SGECs from pSS and controls were stimulated with poly(I:C), IFNα or IFNγ. T cells were sorted from blood and stimulated with IL‐7. CD25 expression was assessed by flow cytometry. Salivary gland explants were cultured for 4 days with anti‐IL‐7R antagonist antibody (OSE‐127) and transcriptomic analysis was performed by using nanostring.ResultsIL‐7 serum level was increased in pSS patients versus controls and was associated with B‐cell biomarkers. IL7R expression was decreased in T cells from pSS patients versus controls. SGECs stimulated with poly(I:C), IFNα, or IFNγ secreted IL‐7. IL‐7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of salivary gland explants showed a correlation between IL7 and IFN expression. Lastly, explants cultured with anti‐IL‐7R antibody showed decreased IFN‐stimulated gene expression.ConclusionThese results suggest an IL‐7‐IFNγ amplification loop involving SGECs and T cells in pSS. IL‐7 was secreted by SGECs stimulated with type 1 or type 2 IFN and, in turn, activate T cells that secrete type 2 IFN. An anti‐IL‐7R antibody decreased the IFN signature in T cells during pSS and could be of therapeutic interest

First-in-Human Study in Healthy Subjects with the Noncytotoxic Monoclonal Antibody OSE-127, a Strict Antagonist of IL-7Rα

International audienceAbstract OSE-127 is a humanized mAb targeting the IL-7Rα-chain (CD127), under development for inflammatory and autoimmune disease treatment. It is a strict antagonist of the IL-7R pathway, is not internalized by target cells, and is noncytotoxic. In this work, a first-in-human, phase I, randomized, double-blind, placebo-controlled, single-center study was carried out to determine the safety, pharmacokinetics, pharmacodynamics, and immunogenicity of OSE-127 administration. Sixty-three healthy subjects were randomly assigned to nine groups: six single ascending dose groups with i.v. administration (0.002–10 mg/kg), a single s.c. treatment group (1 mg/kg), and two double i.v. injection groups (6 or 10 mg/kg). Subjects were followed during <146 d. OSE-127’s pharmacokinetic half-life after a single dose increased from 4.6 (1 mg/kg) to 11.7 d (10 mg/kg) and, after a second dose, from 12.5 (6 mg/kg) to 16.25 d (10 mg/kg). Receptor occupancy was ≥95% at doses ≥0.02 mg/kg, and this saturation level was maintained >100 d after two i.v. infusions at 10 mg/kg. IL-7 consumption was inhibited by OSE-127 administration, as demonstrated by a decreased IL-7 pathway gene signature in peripheral blood cells and by ex vivo T lymphocyte restimulation experiments. OSE-127 was well tolerated, with no evidence of cytokine-release syndrome and no significant alteration of blood lymphocyte counts or subset populations. Altogether, the observed lack of significant lymphopenia or serious adverse events, concomitant with the dose-dependent inhibition of IL-7 consumption by target cells, highlights that OSE-127 may show clinical activity in IL-7R pathway–involved diseases

CLEC-1 is a death sensor that limits antigen cross-presentation by dendritic cells and represents a target for cancer immunotherapy

International audienceTumors exploit numerous immune checkpoints, including those deployed by myeloid cells to curtail antitumor immunity. Here, we show that the C-type lectin receptor CLEC-1 expressed by myeloid cells senses dead cells killed by programmed necrosis. Moreover, we identified Tripartite Motif Containing 21 (TRIM21) as an endogenous ligand overexpressed in various cancers. We observed that the combination of CLEC-1 blockade with chemotherapy prolonged mouse survival in tumor models. Loss of CLEC-1 reduced the accumulation of immunosuppressive myeloid cells in tumors and invigorated the activation state of dendritic cells (DCs), thereby increasing T cell responses. Mechanistically, we found that the absence of CLEC-1 increased the cross-presentation of dead cellassociated antigens by conventional type-1 DCs. We identified antihuman CLEC-1 antagonist antibodies able to enhance antitumor immunity in CLEC-1 humanized mice. Together, our results demonstrate that CLEC-1 acts as an immune checkpoint in myeloid cells and support CLEC-1 as a novel target for cancer immunotherapy

IL-7 receptor blockade blunts antigen-specific memory T cell responses and chronic inflammation in primates

Chronic inflammation often involves reactivation of memory adaptive immune. Here the authors show, using non-human primate models, that a single dose of anti-IL-7 receptor monoclonal antibody that exhibits antagonist but not agonist properties can reduce the frequency of antigen-specific T cell to help repress chronic skin inflammation

Selective SIRPα blockade reverses tumor T cell exclusion and overcomes cancer immunotherapy resistance

International audienceT cell exclusion causes resistance to cancer immunotherapies via immune checkpoint blockade (ICB). Myeloid cells contribute to resistance by expressing signal regulatory protein-α (SIRPα), an inhibitory membrane receptor that interacts with ubiquitous receptor CD47 to control macrophage phagocytosis in the tumor microenvironment. Although CD47/SIRPα-targeting drugs have been assessed in preclinical models, the therapeutic benefit of selectively blocking SIRPα, and not SIRPγ/CD47, in humans remains unknown. We report a potent synergy between selective SIRPα blockade and ICB in increasing memory T cell responses and reverting exclusion in syngeneic and orthotopic tumor models. Selective SIRPα blockade stimulated tumor nest T cell recruitment by restoring murine and human macrophage chemokine secretion and increased anti-tumor T cell responses by promoting tumor-antigen crosspresentation by dendritic cells. However, nonselective SIRPα/SIRPγ blockade targeting CD47 impaired human T cell activation, proliferation, and endothelial transmigration. Selective SIRPα inhibition opens an attractive avenue to overcoming ICB resistance in patients with elevated myeloid cell infiltration in solid tumors