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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

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

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2023-03-11 | PXD037546 | Pride

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

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

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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.

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