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In vitro PI3Kδ inhibition skews CD8 T cell differentiation towards progenitor exhaustion in vivo and reprograms tumor microenvironment metabolism, immune composition, and inflammation [scRNA-seq]

ABSTRACT: In vitro PI3Kδ inhibition using Idelalisib (CAL-101) drives CD8 T cells toward a progenitor exhausted (Tpex) phenotype while resisting terminal exhaustion in vitro. We performed single-cell RNA sequencing and spatial transcriptomics on B16-melanoma tumors and show that CAL-101-treated T cells enhance oxidative phosphorylation, proliferation, and Ifnγ responsiveness. The CAL-101 treated cells deeply infiltrate tumors and upregulate the CXCR3-CXCL10 axis, coinciding with reduced tumor-associated macrophage signatures and increased pro-inflammatory signaling in the tumor microenvironment. CAL-101 reprograms T cell fate and remodels the TME, offering insight into how to improve immunotherapeutic efficacy for solid tumors.

ORGANISM(S): Mus musculus

PROVIDER: GSE286925 | GEO | 2026/06/03

REPOSITORIES: GEO

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In vitro PI3Kδ inhibition skews CD8 T cell differentiation towards progenitor exhaustion in vivo and reprograms tumor microenvironment metabolism, immune composition, and inflammation [Spatial Transcriptomics]

Project description:In vitro PI3Kδ inhibition using Idelalisib (CAL-101) drives CD8 T cells toward a progenitor exhausted (Tpex) phenotype while resisting terminal exhaustion in vitro. We performed single-cell RNA sequencing and spatial transcriptomics on B16-melanoma tumors and show that CAL-101-treated T cells enhance oxidative phosphorylation, proliferation, and Ifnγ responsiveness. The CAL-101 treated cells deeply infiltrate tumors and upregulate the CXCR3-CXCL10 axis, coinciding with reduced tumor-associated macrophage signatures and increased pro-inflammatory signaling in the tumor microenvironment. CAL-101 reprograms T cell fate and remodels the TME, offering insight into how to improve immunotherapeutic efficacy for solid tumors.

2026-06-03 | GSE287743 | GEO

PI3Kδ inhibition potentiates glucocorticoids in B-ALL by decreased receptor phosphorylation and enhanced gene regulation

Project description:Glucocorticoids, including dexamethasone and prednisone, are key components of therapy for B-lymphoblastic leukemia (B-ALL) that work through the glucocorticoid receptor (GR). However, glucocorticoids are not effective for all patients, leading to poor outcomes, and the high doses used in chemotherapy cause many toxicities. We have shown that inhibition of the leukocyte restricted PIK3δ is a promising way to specifically enhance glucocorticoids in B-ALL, with the potential to improve outcomes without increasing toxicities. Here, we show that the PI3Kδ inhibitor idelalisib potentiates both prednisolone and dexamethasone in both B-ALL cell lines and primary patient specimens, particularly at sub-saturating doses. Potentiation is partially explained by a widespread enhancement of glucocorticoid gene regulation, including effector genes that drive B-ALL cell death. Idelalisib causes a reduction in direct phosphorylation of GR at S203 and S226. Ablation of these phospho-acceptor sites enhances glucocorticoid potency. Phosphorylation of S226 inhibits GR DNA binding, indicating that PI3Kδ mediated phosphorylation directly inhibits GR function in part though reduction of DNA binding affinity. Thus, PI3Kδ inhibition improves glucocorticoid efficacy in B-ALL in part by decreasing GR phosphorylation and enhancing DNA binding and downstream gene regulation. Identification of this and other contributing mechanisms will help identify patients who can most benefit clinically from this combination therapy.

2022-10-18 | GSE215385 | GEO

Diffuse Large B Cell Lymphoma cell line with Acquired Resistance to PI3Kδ Inhibitor Idelalisib

Project description:RNAseq profile of TMD8 cell lines resistant to Idelalisib treatment. Idelalisib resistant TMD8 cells were generated by continuous passage in the presence of 1 μM idelalisib for 8 weeks until stable resistance to idelalisib was established. Parallel cultures were grown in the presence of 0.1% DMSO as passage-matched, drug-sensitive control lines. Sensitive and resistant TMD8 cells were clonally isolated through two rounds of single cell limiting dilution

2017-02-17 | GSE93156 | GEO

The PI3Kδ interactome in naïve and activated mouse CD4+ T cells

Project description:Phosphoinositide 3-kinases (PI3Ks) play a central role in adaptive immunity by transducing signals from the T cell antigen receptor (TCR) via production of PIP3. PI3Kδ is a heterodimer composed of a p110δ catalytic subunit associated with a p85α or p85β regulatory subunit and is preferentially engaged by the TCR upon T cell activation. The molecular mechanisms leading to PI3Kδ recruitment and activation at the TCR signalosome remain unclear. In this study, we have used affinity purification coupled with quantitative mass spectrometry to uncover the p110δ interactome in primary CD4+ T cells. Moreover, we have determined how the PI3Kδ interactome changes upon the differentiation of small naïve T cells into T cell blasts expanded in the presence of IL-2.

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Phosphatidylinositol 3-Kinase (PI3K) delta blockade increases genomic instability in B cells

Project description:Activation-induced cytidine deaminase (AID) is a B-cell specific enzyme that targets immunoglobulin (Ig) genes to initiate class switch recombination (CSR) and somatic hypermutation (SHM). Through off-target activity, however, AID has a much broader impact on genomic instability by initiating oncogenic chromosomal translocations and mutations involved in lymphoma development and progression. AID expression is tightly regulated in B cells and its overexpression leads to enhanced genomic instability and lymphoma formation. The phosphatidylinositol 3-kinase (PI3K) δ pathway plays a key role in AID regulation by suppressing its expression in B cells. Novel drugs for leukemia or lymphoma therapy such as idelalisib, duvelisib or ibrutinib inhibit PI3Kδ activity directly or indirectly through inhibition of the Bruton tyrosine kinase (BTK), thus possibly affecting AID expression and, consequently, genomic stability in B cells. Here we show that treatment of primary mouse B cells with idelalisib or duvelisib, and to a lesser extent ibrutinib, enhanced the expression of AID and increased somatic hypermutation (SHM) and chromosomal translocation frequency to the Igh locus and to several AID off-target sites. These effects were both completely abrogated in AID deficient B cells. PI3Kδ inhibitors or ibrutinib increased the formation of AID-dependent tumors in pristane-treated mice. Consistently, PI3Kδ inhibitors enhanced AID expression and translocation frequency to IgH and AID off-target sites in human chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) cell lines, and patients treated with idelalisib showed increased SHM in AID off-targets. In summary, we show that PI3Kδ or BTK inhibitors increase genomic instability in normal and neoplastic B cells by an AID-dependent mechanism. Since such inhibitors are administered for years to patients, their genotoxic potential should be carefully considered while planning therapeutic protocols.

2017-01-31 | GSE77788 | GEO

Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [human]

Project description:Phosphoinositide 3-kinase δ (PI3Kδ) plays key roles in lymphocytes and inhibitors targeting this PI3K have been approved for hematological malignancies. While preclinical data in hematological and solid tumor models have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumor immunity, the impact of PI3Kδi in human solid tumors remains unknown. Here, we assessed the effects of the PI3Kδi AMG319 in patients with early stage head and neck cancer in a neoadjuvant, double-blind and placebo-controlled randomised phase-II trial. We find that PI3Kδ inhibition decreases tumor-infiltrating TREG cells and causes heightened cytotoxic potential of tumor-infiltrating CD8+ and CD4+ T cells. Loss of intratumoral TREG cells and an increase in the frequency of activated TREG cells in the blood post-treatment are indicative of systemic effects on TREG cell tissue retention and maintenance. At the chosen AMG319 dosing, the occurrence of immune-related adverse events caused treatment discontinuation in 43% of drug-treated patients, further suggestive of systemic effects on TREG cells. Consistent with this notion, in a murine syngeneic tumor model, PI3Kδi caused a decrease in TREG cells in both tumor and non-malignant tissues and affected TREG subtype composition, maintenance and functionality.

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Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors [mouse]

2022-03-02 | GSE166149 | GEO

Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors

Project description:Immunomodulatory effects of PI3Kδ inhibition in murine and human solid tumors

| PRJNA699473 | ENA

Suppression of B-cell development genes is key to glucocorticoid efficacy in treatment of acute lymphoblastic leukemia

Project description:Glucocorticoids (GCs) are a central component of combination chemotherapy for childhood B-cell precursor acute lymphoblastic leukemia (B-ALL). GCs work by activating the glucocorticoid receptor (GR), a ligand induced transcription factor, which in turn regulates genes that induce leukemic cell death. Which GR-regulated genes are required for GC cytotoxicity, the pathways that affect their regulation, and how resistance arises are not well understood. Here we systematically integrate the transcriptional response of B-ALL to GCs with a next-generation shRNA screen to identify GC-regulated “effector” genes that contribute to cell death as well as genes that affect the sensitivity of B-ALL cells to dex. This analysis reveals a pervasive role for GCs in suppression of B-cell development genes that is linked to therapeutic response. Inhibition of PI3Kδ, a lynchpin in the pre-B-cell receptor and IL7R signaling pathways critical to B-cell development, with CAL-101 (idelalisib), interrupts a double-negative feedback loop, enhancing GC-regulated transcription to synergistically kill even highly resistant B-ALL with diverse genetic backgrounds. This work not only identifies numerous opportunities for enhanced lymphoid-specific combination chemotherapy that have the potential to overcome treatment resistance, but is also a valuable resource for understanding GC biology and the mechanistic details of GR-regulated transcription. Please note that the cell lines and primary samples were processed and normalized separately.

2017-02-02 | GSE94302 | GEO

RNA-Seq of B-Cell Lines Clones, parental and resistant to Idelalisib or IMGN529

Project description:Idelalisib was the first-in-class PI3Kδ inhibitor and additional compounds are undergoing clinical investigation. To identify modalities to overcome resistance to these agents, we have developed idelalisib-resistant model derived from marginal zone lymphoma cell line (VL51). Cells were kept under idelalisib until acquisition of resistance (VL51-RER) or with no drug (parental). In this experiment we identified the modulated genes between the resistant cell line and the parental counterpart (sensitive to the drug) We invastigated the transcriptomic profiles of parental K1718 B-cell lymphoma cell lines and the same cell line made resistant to Idelalisib. in addition two B-Cells (SUDHL2 and SUDHL4) are made resistant to IMGN529 (Naratuximab emtansine) an antibody-drug conjugate (ADC) incorporating an anti-CD37 monoclonal antibody conjugated to the maytansinoid DM1 as payload.

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