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Bulk RNA sequencing of WT and Pim1 -/- bone-marrow-derived myeloid-derived suppressor cells

ABSTRACT: There is a strong correlation between myeloid derived suppressor cells (MDSCs) and resistance to immune checkpoint blockade (ICB), but the detailed underlying this correlation are largely unknown. Using single-cell RNA-seq analysis in a bilateral tumor model, we found that immunosuppressive myeloid cells with characteristics of fatty acid oxidative metabolism dominate the immune-cell landscape in ICB-resistant subjects. In addition, we uncovered a previously underappreciated role of a serine/threonine kinase, PIM1, in regulating lipid oxidative metabolism via PPARγ-mediated activities. Enforced PPARγ expression sufficiently rescued metabolic and functional defects of Pim1-/- MDSCs. Consistent with this, pharmacological inhibition of PIM kinase by AZD1208 treatment significantly disrupted myeloid cell–mediated immunosuppression microenvironment and unleashed CD8+ T cell–mediated antitumor immunity, which enhanced PD-L1 blockade in preclinical cancer models. PIM kinase inhibition also sensitized non-responders to PD-L1 blockade by selectively targeting suppressive myeloid cells. Overall, we have identified PIM1 as a metabolic modulator in MDSCs that is associated with ICB resistance and can be therapeutically targeted to overcome ICB resistance.

ORGANISM(S): Mus musculus

PROVIDER: GSE166308 | GEO | 2021/02/08

REPOSITORIES: GEO

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Characterization of immune cells from an ICB responder and non-responder using scRNA-seq

Project description:There is a strong correlation between myeloid derived suppressor cells (MDSCs) and resistance to immune checkpoint blockade (ICB), but the detailed underlying this correlation are largely unknown. Using single-cell RNA-seq analysis in a bilateral tumor model, we found that immunosuppressive myeloid cells with characteristics of fatty acid oxidative metabolism dominate the immune-cell landscape in ICB-resistant subjects. In addition, we uncovered a previously underappreciated role of a serine/threonine kinase, PIM1, in regulating lipid oxidative metabolism via PPARγ-mediated activities. Enforced PPARγ expression sufficiently rescued metabolic and functional defects of Pim1-/- MDSCs. Consistent with this, pharmacological inhibition of PIM kinase by AZD1208 treatment significantly disrupted myeloid cell–mediated immunosuppression microenvironment and unleashed CD8+ T cell–mediated antitumor immunity, which enhanced PD-L1 blockade in preclinical cancer models. PIM kinase inhibition also sensitized non-responders to PD-L1 blockade by selectively targeting suppressive myeloid cells. Overall, we have identified PIM1 as a metabolic modulator in MDSCs that is associated with ICB resistance and can be therapeutically targeted to overcome ICB resistance.

2021-02-08 | GSE166309 | GEO

Characterization of myeloid cells in acute and chronic LCMV infection by scRNA-seq

Project description:The immune response to a chronic viral infection is uniquely tailored to balance viral control and immunopathology. The role of myeloid cells in shaping the response to chronic viral infection, however, is poorly understood. Single-cell RNA sequencing of myeloid cells during acute and chronic LCMV infection was performed to address this question. We discovered a cluster of suppressive neutrophils that is enriched in chronic versus acute infection. Furthermore, suppressive neutrophils highly expressed the gene encoding PIM1, a kinase known to promote mitochondrial fitness and cell survival. Pharmacological inhibition of PIM1 selectively diminished suppressive neutrophil-mediated immunosuppression without affecting the function of monocytic myeloid derived suppressor cells (M-MDSCs). Decreased accumulation of suppressive neutrophils led to increased CD8 T cell function and viral control. Mechanistically, PIM kinase activity was required for maintaining fused mitochondrial networks in suppressive neutrophils, but not in M-MDSCs, and loss of PIM kinase function caused increased apoptosis of suppressive neutrophils.

2021-05-05 | GSE167204 | GEO

Tumor-Infiltrating Myeloid Cells Confer de novo Resistance to PD-L1 Blockade through EMT-stromal and Tgf-beta Dependent Mechanisms

Project description:Most bladder cancers are poorly responsive to immune checkpoint blockade (ICB) of PD-L1. Thus, there is a need to define mechanisms of de novo resistance including contributions from tumor infiltrating immune cells. In this study, we used single-cell transcriptional profiling to map and define infiltrating myeloid cells in 10 human bladder tumors. Human data sets were qualitatively compared with myeloid data sets from the carcinogen (BBN) induced mouse model of bladder cancer which we have demonstrated to be poorly responsive to PD-L1 blockade. We previously established a signature of acquired ICB resistance which we apply here to new human and murine tumor data sets that have not received prior ICB (or systemic treatment). In doing so, we reveal conservation in EMT-stromal core genes and TGF beta signaling between human and mouse myeloid cells consistent with signatures of de novo ICB resistance. Untreated BBN tumors were highly infiltrated with M0-M2 macrophages, low in T-NK infiltration and modeled a patient subpopulation with poor survival outcome. Concordantly, the combined targeting of TGFb + PD-L1 reverted immune cell exclusion and resulted in increased survival and delayed BBN mouse tumor progression. These data constitute the stromal and myeloid cell populations as providing a coordinate mechanism de novo resistance to PD-L1 blockade in a TGF-beta dependent manner.

2022-10-17 | GSE211388 | GEO

Transcriptome analysis PIM kinase inhibition vs degradation

Project description:PIM kinases have important pro-tumorigenic roles and mediate several oncogenic traits, including cell proliferation, survival, and chemotherapeutic resistance. As a result, multiple PIM inhibitors have been pursued as investigational new drugs in cancer; however, response to PIM inhibitors in solid tumors has fallen short of expectations. We found that inhibition of PIM kinase activity stabilizes protein levels of all three PIM isoforms (PIM1/2/3), and this can promote resistance to PIM inhibitors and chemotherapy. To overcome this effect, we designed PIM proteolysis targeting chimeras (PROTACs) to target PIM for degradation. PIM PROTACs effectively downmodulated PIM levels through the ubiquitin-proteasome pathway. Importantly, degradation of PIM kinases was more potent than inhibition of catalytic activity in inducing apoptosis in prostate cancer cell line models. In conclusion, we provide evidence of the advantages of degrading PIM kinases versus inhibiting their catalytic activity to target the oncogenic functions of PIM kinases.

2023-12-04 | GSE237256 | GEO

Loss of Pim1 Imposes a Hyperadhesive Phenotype on Endothelial Cells

Project description:Background: PIM1 is a constitutively active serine-threonine kinase regulating cell survival and proliferation. Increased PIM1 expression has been correlated with cancer metastasis by facilitating migration and anti-adhesion. Endothelial cells play a pivotal role in these processes by contributing a barrier to the blood stream. Here, we investigated whether PIM1 regulates mouse aortic endothelial cell (MAEC) monolayer integrity. Methods: Pim1-/-MAEC were isolated from Pim1 knockout mice and used in trypsinization-, wound closure assays, electrical cell-substrate sensing, immunostaining, cDNA transfection and as RNA source for microarray analysis. Results: Pim1-/-MAEC displayed decreased migration, slowed cell detachment and increased electrical resistance across the endothelial monolayer. Reintroduction of Pim1- cDNA into Pim1-/-MAEC significantly restored wildtype adhesive characteristics. Pim1-/--MAEC displayed enhanced focal adhesion and adherens junction structures containing vinculin and M-NM-2-catenin, respectively. Junctional molecules such as Cadherin 13 and matrix components such as Collagen 6a3 were highly upregulated in Pim1-/- cells. Intriguingly, extracellular matrix deposited by Pim1-/- cells alone was sufficient to induce the hyperadhesive phenotype in wildtype endothelial cells. Conclusion: Loss of Pim1 induces a strong adhesive phenotype by enhancing endothelial cell-cell and cell-matrix adhesion by the deposition of a specific extracellular matrix. Targeting PIM1 function therefore might be important to promote endothelial barrier integrity. Pim-1-/- mouse aortic endothelial cells were compared to wildtype cells

2012-10-29 | E-GEOD-32059 | biostudies-arrayexpress

Inhibiting ACK1-mediated phosphorylation of C-terminal Src kinase counteracts prostate cancer immune checkpoint blockade resistance

Project description:Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK pY18 phosphorylation and spontaneous activation of CD8+ and CD4+ T cells, resulting in inhibited growth of transplanted ICB-resistant tumours. Furthermore, ICB treatment of castration-resistant prostate cancer (CRPC) patients results in re-activation of ACK1/pY18-CSK signalling, confirming the involvement of this pathway in ICB insensitivity. An ACK1 small-molecule inhibitor, (R)-9b, recapitulates inhibition of ICB-resistant tumours, which provides evidence for ACK1 enzymatic activity playing a pivotal role in generating ICB resistance. Overall, our study identifies an important mechanism of ICB resistance and holds potential for expanding the scope of ICB therapy to tumours that are currently unresponsive.

2023-03-11 | PXD037546 | Pride

Proviral integration site for Moloney murine leukemia virus (PIM) kinases promote human T helper 1 cell differentiation

Project description:The aim of the dataset was to study on genome-wide level the effect of PIM kinase (PIM1+PIM2+PIM3) knockdown in gene expression on early differentiation of human cord blood derived CD4+ T cells cultured under Th1 (Act+IL12) polarizing conditions. Total RNA from PIM1+PIM2+PIM3 siRNA treated cord blood CD4+ T cells 6 hours after culturing the cells in activating (antiCD3+antiCD28) plus IL-12 (Th1) or IL-4 (Th2) conditions was compared to total RNA from nonspecific control siRNA treated cells. Samples from 3 biological replicates were analysed.

2012-12-05 | E-GEOD-40542 | biostudies-arrayexpress

Proviral integration site for Moloney murine leukemia virus (PIM) kinases promote human T helper 1 cell differentiation

2012-12-05 | GSE40542 | GEO

RNA-seq analysis of WT and Pim1-/- BMDMs

Project description:The Pim (proviral integration site for Moloney murine leukemia virus) proteins form a serine threonine kinase family that regulates cell proliferation, migration and cell survival. Here we demonstrate for the first time that a Pim1 kinase plays an essential role in antiviral innate immune responses. Specifically, our in vivo, in vitro and RNA-sequencing analyses showed that Pim1 was quickly upregulated after Toll-like receptor (TLR) stimulation in a NF-kB-dependent manner and then promoted IFN-b production by forming a cell-surface complex composed of TRIF-signaling molecules and IRF3 that promoted IRF3 phosphorylation, nuclear translocation, and IFN-b production. As shown by Pim1 knockdown and knockout, Pim1 was essential for this role but its kinase activity was not involved. Pim1-deficiency increased the susceptibility of mice to poly I:C-induced sepsis. Our study uncovers a previously unrecognized role for Pim1 in antiviral innate immune responses, thus providing a new target for controlling viral infection.

2022-12-14 | GSE195582 | GEO

Proteomics of Day 6 IL-2 or IL-15 expanded wild-type and Pim1/Pim2 double knockout CD8+ T cells.

Project description:T cell antigen-receptor (TCR) and cytokine receptor engagement trigger large changes in Serine/Threonine kinase signalling networks to drive T cell activation and differentiation. The role of only few kinase signalling pathways have been studied in detail, and in this context, Pim kinases are an interesting, yet understudied, family of Serine/Threonine kinases, with reported roles in key processes including survival, proliferation, metabolism across a range of cell types. T lymphocytes predominantly express PIM1 and PIM2, which are rapidly induced by TCR, costimulation and cytokine signalling. Using high-resolution mass spectrometry and RNAseq we systematically examine the impact of Pim1/Pim2 double deficiency on in vitro differentiated cytotoxic T lymphocytes (CTL) expanded in the cytokines IL-2 and IL-15 to generate effector or memory T cells respectively. We find that Pim kinases are dispensable for IL-15-driven memory cell differentiation, but that Pim1/2-deficiency has a selective impact on the transcriptome and proteome of IL-2 driven effector CD8 T cells. ~75% of Pim kinase-regulated proteins were not predicted by differences in mRNA in IL-2 expanded CTL. These included proteins that are key for effector cell function: glucose transporters SLC2A1 and SLC2A3 and key effector molecules Granzyme A and B. We find that Pim kinases have this effect via control of protein translation. Another key finding was that the mRNA for key T cell homing receptors Ccr7, S1pr1 and CD62L was increased in Pim1/2-deficienct T cells and that this functionally enhancing homing to secondary lymphoid organs.

2024-04-15 | PXD051213 | Pride

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