Cell-targeted PD-1 agonists are potent NK cell inhibitors
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ABSTRACT:
PROVIDER: PRJNA1216245 | ENA |
REPOSITORIES: ENA
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Project description:We have generated a novel targeted bispecific PD-1 molecule, to achieve tissue-specific immune suppression for the treatment of immune-mediated inflammatory diseases. These targeted PD-1 agonists have shown potent T cell inhibition and here we describe an additional effect on NK cell activation. We show that PD-1 pathway activation modifies NK cell gene expression and decreases their inflammatory and cytotoxic functions. Targeted PD-1 agonist molecules, inhibiting T cells and NK cells in a tissue-specific manner offer a new promising treatment for autoimmune and inflammatory diseases.
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Project description:The PD-1/PD-L1 pathway is a key immune checkpoint that regulates T cell activation. There is strong rationale to develop PD-1 agonists as therapeutics against autoimmunity, but progress in this area has been limited. Here, we generated T cell receptor (TCR) targeting, PD-1 agonist bispecifics called ImmTAAI molecules that mimic the ability of PD-L1 to facilitate the colocalization of PD-1 with the TCR complex at the target cell-T cell interface. PD-1 agonist ImmTAAI molecules specifically bound to target cells and were highly effective in activating the PD-1 receptor on interacting T cells to achieve immune suppression. Potent PD-1 antibody ImmTAAI molecules closely mimicked the mechanism of action of endogenously expressed PD-L1 in their localization to the target cell-T cell interface, inhibition of proximal TCR signaling events, and suppression of T cell function. At picomolar concentrations, these bispecifics suppressed cytokine production and inhibited CD8+ T cell-mediated cytotoxicity in vitro. Crucially, in soluble form, the PD-1 ImmTAAI molecules were inactive and, hence, could avoid systemic immunosuppression. This study outlines a promising new route to generate more effective, potent, tissue-targeted PD-1 agonists that can inhibit T cell function locally with the potential to treat autoimmune and chronic inflammatory diseases of high unmet need.
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Project description:Ovarian cancer (OC) is the fifth leading cause of cancer-related death and High-Grade Serous Ovarian Carcinoma (HGSOC) is its most common histotype. Current therapies are ineffective, and most patients develop a recurrence within a few years. Moreover, if outstanding results can be obtained with immune-checkpoint blockade strategies (mainly PD-1/PD-L axis) in immunotherapeutic protocols for several aggressive tumors, clinical trials didn’t show good results with HGSOC patients so far. Here we analysed, by multiparametric flow cytometry, NK cells derived from peripheral blood, peritoneal fluid, tumor tissue, and metastatic tissue of a large cohort of HGSOC patients, in order to define how NK cells could be leveraged to improve HGSOC immunotherapy. We identified new PD-1+NK subsets occurring in HGSOC patients, but absent in healthy donors, characterized by a CD56dimNKG2A+KIR+/-NKp46+CD57low phenotype and ineffective anti-tumor response against autologous HGSOC cells. This impairment could be rescued by treatment with a combination of anti-PD-1/PD-Ls, NKG2A, and KIRs mAbs. PD-1+ NK cells were enriched in the metastatic niche and high levels of tumor-infiltrating PD-1+ NK cells correlate with a worse outcome, suggesting a role for PD-1 in metastatic promotion/progression. Our data demonstrate the existence of novel tumor-infiltrating PD-1+ NK cell subsets in HGSOC patients, which are inversely related to patient outcome, showing the importance of these NK subsets. These subsets show indeed impaired anti-tumor activity, which can be rescued by combined ICs blockade, paving the way for more successful NK cell-based immunotherapy in OC patients.
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Project description:This experiment aims to investigate how the overexpression of PD-L1 and SCE enhances the cytotoxic activity of CAR-NK cells against tumor cells. Pathway enrichment analysis revealed that CAR-NK cells with reduced HLA-ABC and overexpressed PD-L1 showed enrichment in proliferation and pro-inflammatory pathways. In contrast, CAR-NK cells with reduced HLA-ABC and overexpressed SCE exhibited enrichment in homeostasis-related pathways. On the other hand, cellular stress pathways were more prominently enriched in HLA-ABC reduced CAR NK cells following co-culture with target cells.
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Project description:Chronic lymphocytic leukaemia (B-CLL) is associated with immune suppression and functional impairment of NK cells, due partly to the reduced expression of activating receptors. We studied the profile of inhibitory checkpoint receptor expression on NK cells from patients with B-CLL. Single, dual and triple expression of the checkpoint receptors PD-1, CTLA-4, LAG-3 and CD96 was increased in patients compared to age-matched healthy controls. PD-1pos cells were present within the late differentiated CD56dim NK pool and showed strong downregulation of all activatory receptors whilst transcriptional profiles revealed a profile of strong receptor signalling. PD-1pos NK cells demonstrated impaired cytokine production and degranulation following target engagement and transfection of PD-1 into NK cell lines directed suppressed cytotoxic function. Importantly, blockade of PD-1:PD-L1 engagement acted to partially reverse these functional defects. These results reveal expression of inhibitory checkpoint receptors to be a new mechanism of NK cell dysfunction in patients with cancer and indicate a potential therapeutic role for single or combinatorial checkpoint blockade to boost immune function in patients with B-CLL.
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Project description:The objective was to determine if there are differences in gene expression in PD-L1+ and PD-L1- NK cells after co-incubation of NK cells with target K562 myeloid leukemia cells.
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